Inflammatory/Autoimmune Disease Archives

Previously, he was a postdoc and project scientist at UC San Diego, where he also received his PhD

Related Disease
Immune Disorders, Inflammatory Bowel Disease, Inflammatory/Autoimmune Disease, Multiple Sclerosis, Type 1 Diabetes

Phenomena or Processes
Cell Biology

Anatomical Systems and Sites
Immune System and Inflammation

Techniques and Technologies
Biochemistry

Dennis works in the Bradley lab where he investigates autoimmune disease and immune checkpoint modulators that can be used to block autoimmune disease or promote an immune response to virus or tumor cells.

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Showing 3 of 3

IFN-β Selectively Inhibits IL-2 Production through CREM-Mediated Chromatin Remodeling.

Otero DC, Fares-Frederickson NJ, Xiao M, Baker DP, David M

J Immunol 2015 Jun 1 ;194(11):5120-8

IRF7-dependent IFN-β production in response to RANKL promotes medullary thymic epithelial cell development.

Otero DC, Baker DP, David M

J Immunol 2013 Apr 1 ;190(7):3289-98

T cell-intrinsic and -extrinsic contributions of the IFNAR/STAT1-axis to thymocyte survival.

Moro H, Otero DC, Tanabe Y, David M

PLoS One 2011 ;6(9):e24972

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Guy Salvesen earned his PhD in biochemistry from Cambridge University in 1980. He conducted postdoctoral research at Strangeways Laboratory and MRC Laboratory of Molecular Biology in Cambridge, followed by further post-doctoral training at the University of Georgia. In 1991 he was appointed Assistant Professor at Duke University. Dr. Salvesen was recruited to Sanford-Burnham Medical Research Institute in 1996, where he is professor and director of the Apoptosis and Cell Death Research Program and dean of the Graduate School of Biomedical Sciences. He also holds an adjunct position as professor in the Department of Pathology at the University of California, San Diego.

Education

1981: PhD, Cambridge University, England, Biology
1977: B. Sc., London University, London, England, Microbiology

Other Appointments

Adjunct Professor, Department of Pathology, University of California, San Diego

Honors and Recognition

2014: Organizer, Keystone Meeting on Cell Death, February
2013: IUBMB Gold Medal Recipient, October
2010: Keynote Speaker, European Cell Death Organization Conference,
2010: Keynote Speaker, Gordon Research Conference on Cell Death
2009: Lifetime Achievement Award of the International Proteolysis Society
2008: Keynote Speaker, Queenstown Molecular Biology Conference
2008: Chair, Gordon Research Conference on Cell Death
2005: Helmut Holzer Memorial Prize
1999: International Proteolysis Society, Elected Secretary
1999: Keynote Speaker, Gordon Research Conference on Matrix Metalloproteinases
1988: American Association for the Study of Liver Diseases, State of the Art Lecture
1996: Chair, Gordon Research Conference on Proteolytic Enzymes and Their Inhibitors

Related Disease
Cancer, Inflammatory/Autoimmune Disease, Neurodegenerative and Neuromuscular Diseases, Pancreatic Cancer, Skin Cancer and Melanoma, Structural Biology

Phenomena or Processes
Apoptosis and Cell Death, Caspase Family, Cytokines, Inflammation, Protein Structure-Function Relationships, Proteolytic Pathways, Ubiquitin, Ubiquitin Protease System and Ubiquitin-like Proteins

Research Models
Bacteria, Human Cell Lines, Mouse, Mouse Cell Lines, Primary Human Cells

Techniques and Technologies
Biochemistry, Cellular and Molecular Imaging, Chemical Biology, Fluorescence Microscopy, Mass Spectrometry, Protein Engineering, Protein Structure Prediction, Protein-Protein Interactions, Proteomics

The human body contains cells with different life expectancies. Some (white blood cells or skin, for example) are programmed to rapidly die and be replaced. Others (such as nerve cells) are programmed to survive the lifetime of the individual and are seldom replaced. Dr. Salvesen’s research focuses on the central role enzyme pathways play in the life and death of cells. When death pathways slow down in cells that are normally programmed to die, cancer results. Conversely, when death pathways become overactive in cells that are programmed to survive, degenerative disease occurs. Dr. Salvesen’s laboratory focuses on understanding the fundamental molecular interactions that occur within these enzyme pathways. This knowledge is used to engineer synthetic compounds to stimulate cell destruction in cancer cells, or delay cell destruction in neurodegenerative diseases and stroke.

Guy Salvesen’s Research Report

Structure and Function of Proteases and Their Natural Inhibitors

Our research seeks to delineate the structure –> activity –> function algorithm as it applies to proteases and their inhibitors. Our laboratory has very broad interests in principles of proteolysis in humans, and we take multi-pronged approaches to research on proteases and their inhibitors.

Apoptosis

In one approach we apply basic biochemical knowledge to investigate newly emerging principles of proteolysis in human systems. This research is currently dissecting the proteolytic components of the intracellular pathway that lead to apoptotic cell death. Programmed cell death monitors the growth of new cells and the elimination of old ones. This program contains a number of proteolytic steps that are essential for efficient execution of the death pathway. Thus the proteases of the pathway – the caspases – are involved in the normal maintenance of correct cell number, and are therefore implicated in a number of pathologic and physiologic conditions. Using the techniques of protein chemistry, enzymology, crystallography, and recombinant DNA methodologies, we analyze the basic mechanism utilized by caspases to promote cell death pathways, and the mechanisms and specificity of the natural inhibitors that control them.

Cell Signaling

Modification of proteins by the small ubiquitin-like modifier SUMO is a dynamic and reversible process. The SUMO cycle begins when SUMO precursors are processed to remove short C-terminal extensions, thereby uncapping the C-terminal Gly-Gly motif that is essential for conjugation. SUMO ligases conjugate the protein, via its C-terminal carboxylate, to the side-chain lysine of target proteins to generate an isopeptide linkage. Eventually, SUMO is removed intact from its substrate SUMOylated proteins, and so the SUMOylation/deSUMOylation cycle regulates SUMOs function. A group of proteases known as SENPs are involved in both the activation of SUMO precursors (endopeptidase cleavage) and deconjugation of the targets (isopeptidase cleavage). Our laboratory is currently involved in projects to define the mechanisms that regulate SENP activity and access to their natural substrates.

Technology Development

The principle of proteolysis in vivo is to instigate irreversible changes to a set of protein substrates that alters their function and generates the required biological event. The sum total of the proteases and their target substrates operating in a physiologic pathway therefore defines the global event. Consequently, the identity of the substrate cleavages defines the proteases acting on them. We are developing proteomics-based methodologies, including selective protein labeling, multi-dimensional electrophoresis, and mass spectrometry techniques, to identify the products of proteolysis in vivo.

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Showing 3 of 3

SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML.

Fasci D, Anania VG, Lill JR, Salvesen GS

Sci Signal 2015 Jun 9 ;8(380):ra56

FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.

Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ, Green DR, Salvesen GS

Biochem J 2011 Feb 1 ;433(3):447-457

Emerging principles in protease-based drug discovery.

Drag M, Salvesen GS

Nat Rev Drug Discov 2010 Sep ;9(9):690-701

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Dr. Tautz develops novel drugs targeting protein tyrosine phosphatases that are implicated in cancer, thrombosis, and Alzheimer’s disease.

Dr. Tautz earned his PhD in Organic Chemistry and Biochemistry from the University of Karlsruhe (Germany) with Dr. Janos Retey in 2002. He continued his research at the Burnham Institute with Dr. Tomas Mustelin, first as a postdoc and later as a staff scientist. In 2009 Dr. Tautz joined the faculty of the Sanford Burnham Prebys Medical Discovery Institute.

Education

2002: PhD, University of Karlsruhe, Germany, Chemistry, Biochemistry
1997: MS, University of Karlsruhe, Germany, Chemistry

Funding Awards and Collaborative Grants

American Heart Association Innovative Research Grant

Honors and Recognition

2014: Semifinalist, Stadtman Investigator Search, National Institutes of Health
2008/2006 : Society for Biomolecular Sciences Travel Awards
2006: American Chemical Society Travel Award
2006: William and Lillian Fishman Award for Exceptional Postdoctoral Research
2002: PhD in Chemistry magna cum laude, University of Karlsruhe, Germany

Related Disease
Alzheimer’s Disease, Cancer, Cardiovascular Diseases, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma, Neurodegenerative and Neuromuscular Diseases

Many human diseases stem from abnormalities in the activities of protein kinases and protein phosphatases. While efficacious therapeutics targeting protein kinases have been successfully used in the clinic (e.g., Gleevec), effective strategies to target specific protein phosphatases are still elusive. Dr. Tautz’ laboratory works on novel, more effective approaches to target these important enzymes. He focuses on protein tyrosine phosphatases implicated in cancer, thrombosis, autoimmunity, and Alzheimer’s disease.

Lutz Tautz’s Research Report

1. Discovery of a Novel Drug Target in Arterial Thrombosis

Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. In collaboration with researchers at the University of Liege in Belgium (Drs. Souad Rahmouni and Cecile Oury), we recently identified DUSP3 (also known as VHR) as a major regulator in platelet signaling and thrombosis. Intriguingly, bleeding was not affected by DUSP3 deficiency in mice, suggesting that DUSP3 plays a key role in arterial thrombosis, but is dispensable for primary hemostasis. We develop a specific small-molecule inhibitor of DUSP3 that effectively inhibited platelet aggregation in human platelets, thereby phenocopying the effect of DUSP3 deficiency in murine platelets. We are now poised to optimize this compound for in vivo studies in order to provide proof-of-concept for a novel and potentially safer antiplatelet strategy based on DUSP3.

Publications:

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis Musumeci L et al. Circulation. 2015 Feb 17;131(7):656-68.
Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy. Tautz L et al. Bioorg Med Chem. 2015 Jun 15;23(12):2786-97.

2. Discovery of a Novel Mechanism in T Cell Activation

PTPs are crucial for maintaining the homeostasis of the immune system, including the regulation of antigen receptor-mediated lymphocyte activation and cytokine-induced differentiation. The lymphoid tyrosine phosphatase (LYP, PTPN22) is a critical negative regulator of T cell antigen receptor signaling. A single-nucleotide polymorphism (SNP) in PTPN22 was shown to correlate with the incidence of various autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. First, we helped to demonstrate that the disease-associated allele is a gain-of-function mutant, i.e. a better inhibitor of T cell receptor activation. Then, we developed a specific chemical probe of LYP which we utilized to identify the associated mechanism that leads to increased LYP activity. In contrast to what was known from work in mice, we showed that in human cells LYP needs to dissociate from CSK in order to inhibit T cell activation. We also showed that our LYP inhibitor acts by stabilizing a unique inactive conformation of LYP.

Publications:

Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Vang T et al. Nat Genet. 2005 Dec;37(12):1317-9.
In Silico Screening for PTPN22 Inhibitors: Active Hits From an Inactive Phosphatase Conformation. Wu S et al. ChemMedChem. 2009 Mar;4(3):440-4.
Inhibition of Lymphoid Tyrosine Phosphatase by Benzofuran Salicylic Acids. Vang T et al. J Med Chem. 2011 Jan 27;54(2):562-71.
LYP inhibits T cell activation when dissociated from CSK. Vang T et al. Nat Chem Biol. 2012 Mar 18;8(5):437-46.

3. Chemical Probe Development for Cancer Research

We have been working on chemical probes for cancer targets for several years (e.g., VHR, HePTP). Currently, we focus on the role of SHP2 in leukemia and breast cancer. PTPN11, the gene encoding SHP2, has been widely recognized as an oncogene. Germline mutations in PTPN11 were first observed in ~50% of cases of Noonan syndrome, an autosomal dominant developmental disorder with increased risk of malignancy. Numerous somatic gain-of-function mutations in PTPN11 have been identified in various leukemias. Hyperactivated SHP2 was also found in several types of solid tumors, including breast cancer. Previously reported SHP2 inhibitors lack efficacy in cancer cells and/or selectivity over related homologs. Novel SHP2 antagonists are needed for proof-of-principle studies that support a therapeutic approach based on SHP2. We have identified novel SHP2 lead compounds with significantly improved efficacy and selectivity. Currently, we optimize these compounds to make them suitable for in vivo studies.

Publications:

Multidentate Small-Molecule Inhibitors of Vaccinia H1-Related (VHR) Phosphatase Decrease Proliferation of Cervix Cancer Cells. Wu S et al. J Med Chem. 2009 Nov 12;52(21):6716-23.
Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids. Bobkova EV et al. ACS Med Chem Lett. 2011 Feb;2(2):113-118.
A Specific Inhibitor of Hematopoietic Protein Tyrosine Phosphatase Augments ERK1/2 and p38 Activation in vivo. Sergienko E et al. ACS Chem Biol. 2012 Feb 17; 7(2): 367–377.
Protein tyrosine phosphatases: structure, function, and implication in human disease. Tautz L et al. Methods Mol Biol. 2013;1053:179-221.

4. Targeting STEP in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by a progressive loss of cognitive function. The FDA has approved four drugs to treat the cognitive deficits in AD (donepezil, galantamine, rivastigmine, and memantine). However, none of these drugs halt disease progression. Our collaborator Dr. Paul Lombroso (Yale) identified the STriatal-Enriched Phosphatase (STEP) as a novel therapeutic target involved in the initial synaptic dysfunction that occurs prior to loss of neurons. His work suggests that inhibition of STEP could provide a disease-modifying strategy and early treatment option for AD. We recently received funding from the Alzheimer’s Association to develop a high-throughput assay to screen large chemical libraries for compounds that inhibit STEP function in neuronal cells. Once such compounds are identified, we will test their potential to reverse the biochemical and cognitive defects in AD animal models.

Publications:

Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer’s Disease. Xu J et al. PLoS Biol. 2014 Aug 5;12(8):e1001923.

Select Publications

Showing 3 of 3

Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy.

Tautz L, Senis YA, Oury C, Rahmouni S

Bioorg Med Chem 2015 Jun 15 ;23(12):2786-97

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

Musumeci L, Kuijpers MJ, Gilio K, Hego A, Théâtre E, Maurissen L, Vandereyken M, Diogo CV, Lecut C, Guilmain W, Bobkova EV, Eble JA, Dahl R, Drion P, Rascon J, Mostofi Y, Yuan H, Sergienko E, Chung TD, Thiry M, Senis Y, Moutschen M, Mustelin T, Lancellotti P, Heemskerk JW, Tautz L, Oury C, Rahmouni S

Circulation 2015 Feb 17 ;131(7):656-68

Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer’s disease.

Xu J, Chatterjee M, Baguley TD, Brouillette J, Kurup P, Ghosh D, Kanyo J, Zhang Y, Seyb K, Ononenyi C, Foscue E, Anderson GM, Gresack J, Cuny GD, Glicksman MA, Greengard P, Lam TT, Tautz L, Nairn AC, Ellman JA, Lombroso PJ

PLoS Biol 2014 Aug ;12(8):e1001923

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Dr. Carl F. Ware received his PhD in Molecular Biology and Biochemistry from the University of California, Irvine in 1979. From 1979-81, while supported by a prestigious National Research Service Award from the NIH, Dr. Ware conducted research at the University of Texas Health Science Center in San Antonio in membrane biochemistry and the complement system with Dr. W. Kolb. In 1981, Dr. Ware joined the research groups of Dr. Jack Strominger and Dr. Tim Springer at Dana-Farber Cancer Institute, Harvard Medical School, where he developed monoclonal antibodies to discover several membrane proteins associated with T cell function. Dr. Ware established his research laboratory in 1982, as an Assistant Professor of Immunology in the Biomedical Sciences Program at the University of California, Riverside, advancing to full professor before joining the La Jolla Institute for Allergy and Immunology in 1996 as Head of the Division of Molecular Immunology. Dr. Ware also holds a joint appointment in the Department of Biology at the University of California, San Diego. In 2010, Dr. Ware was recruited to Sanford Burnham Prebys as Director of the Infectious and Inflammatory Diseases Center, where he continues his research in molecular immunology and virology. Dr. Ware also advises several biotechnology companies on approaches to drug development and most recently, he founded CoSignaling Pathway Research, Inc., to help translate his discoveries into new therapies for cancer, infectious and autoimmune diseases.

Related Disease
Arthritis, Breast Cancer, Cancer, Crohn’s Disease (Colitis), Infectious Diseases, Inflammatory Bowel Disease, Inflammatory/Autoimmune Disease, Inherited Disorders, Leukemia/Lymphoma, Myeloma, Pathogen Invasion, Psoriasis, Systemic Lupus Erythematosus, Type 1 Diabetes

Techniques and Technologies
Transplantation

Research in the Laboratory of Molecular Immunology is directed at defining the intercellular communication pathways controlling immune responses. Our work is focused on the Tumor Necrosis Factor (TNF)-related cytokines in regulating decisions of cell survival and death, especially in responses to viral pathogens. Translational research is redirecting the communication networks of TNF superfamily to alter the course of autoimmune and infectious disease and cancer.

Carl Ware’s Research Report

TNF Superfamily of Cytokines

The laboratory’s work has lead to the discovery of several members of TNF cytokine superfamily and their signaling circuitry. The importance of the signaling circuitry of the immediate family of TNF related cytokines is apparent in the diversity of physiological systems dependent upon their function. TNF, LTαβ and LIGHT modulate lymphoid organ development, homeostasis, and architecture representing cellular interactions between lymphocytes, antigen presenting cells and surrounding stromal cells. These cellular interactions initiate effective host defenses to viral pathogens. Moreover, our studies on modulation the TNF/LT related cytokines by viruses is revealing novel targets for intervention in autoimmune diseases.

The Lymphotoxin-αβ and LIGHT cytokine systems, along with TNF, form an integrated cytokine-signaling circuit that regulates the development and homeostasis of the innate and adaptive immune systems (Fig. 1). The TNF related cytokines assemble as trimers and cluster their specific cell surface receptors to initiate signaling. Both TNF and LTα bind two TNF receptors (TNFR) type 1 and 2. LTα forms a heterotrimer with membrane anchored LTβ creating a ligand with distinct receptor specificity. In contrast with LTα, the LTα1β2 heterotrimer signals exclusively via the LTβ receptor (LTβR), which is expressed on stromal and myeloid cells. LTβR is also activated by another ligand, LIGHT, which binds to the herpesvirus entry mediator (HVEM). A viral ligand, the envelope glycoprotein D of Herpes Simplex virus also binds to HVEM. The signaling pathways activated by these receptors show commonality, yet distinctions exist that reveal each pathway’s unique contribution to cellular differentiation. A goal of the laboratory is to develop a full understanding of the integrated physiological functions of these cytokines in disease pathogenesis. Targeting TNF aids in controlling inflammation in some but not all autoimmune diseases, thus, elucidating the fundamental properties of these communication circuits may provide new opportunities in the clinic.

Fig. 1 Integrated circuits: TNF/LT related cytokines. TNF, LTβ and LIGHT are type 2 membrane proteins that assembled as trimers that engage transmembrane receptors with a characteristic cysteine-rich domain. This family shows significant cross-usage of ligands and receptors (binding specificity is indicated by arrows). LIGHT is a paralog of LTβ; HVEM, herpesvirus entry mediator; DcR3, decoy receptors 3 also binds Fas Ligand and TL1A (not shown). TNFR1 contains a death signaling domain, whereas TNFR2, LTβR and HVEM contain a peptide interaction motif for the TRAF adaptors.

Receptor Signaling: TNF Receptors Are Allosteric Regulators of Ubiquitin E3 Ligases

The NFkB inducing kinase (NIK) is the key molecule that controls the non-canonical pathway of NFkB activation by several members of the TNF receptor superfamily through direct binding of the TRAF adaptors. In unstimulated cells, constitutive proteosome degradation prevents NIK from accumulation. Degradation of NIK is mediated by a cytosolic ubiquitin E3 ligase comprised of TNFR-associated factors (TRAF), a family of Zinc RING finger proteins. The ubiquitin:NIK E3 ligase is a multisubunit complex comprised of TRAF3 and TRAF2 in association with the cellular inhibitors of apoptosis (cIAP)-1 and 2. In the complex, TRAF3 binds NIK, and TRAF2 engages cIAP. All three subunits contain RING and Zn finger motifs that are required for ubiquitin E3 ligase activity and NIK turnover. This highly efficient ubiquitin:NIK E3 ligase maintains NIK at vanishing low levels, below detection by the most sensitive assays. Thus, TRAF3 and TRAF2 function as inhibitors of NIK suppressing NFkB activation.

The trimeric ligands of the TNF superfamily initiate signaling by clustering of their cognate receptors; however, the translation of receptor ligation to the activation of intracellular signals is unknown. TRAF3 and TRAF2 directly associate with LTβR and other receptors rapidly after ligand binding, implicating their role in signaling. Our work revealed that the TRAF3 binding site for NIK is located in the common receptor-binding crevice, thus the recruitment of TRAF3 to the ligated LTβR directly competes with NIK for TRAF3 (Fig.2). Similarly, recruitment of TRAF2 to the LTβR displaced cIAP from TRAF2. Furthermore, TRAF2 and TRAF3 recruited to the LTbR cytosolic domain were polyubiquitinated and degraded. Polyubiquitination and degradation of TRAF3 and TRAF2 was dependent on the TRAF2 RING domain. NIK liberated from its association with TRAF3 engaged IKKα propagating the serine kinase cascade leading to the formation of the active NF-kB p52/RelB transcriptional complex. Together, these results indicate the LTβR serves as an allosteric regulator by competitively displacing the substrate NIK and redirecting the specificity of the ubiquitin:NIK E3 ligase to ubiquitinate the TRAF molecules.

Fig. 2 Allosteric regulation of ubiquitin:NIK and TRAF3 E3 ligase by the LTβR. NIK is maintained at low levels in non-stimulated cells by Ub-dependent degradation via Ubiquitin:NIK E3 ligase consisting of TRAF3-TRAF2-cIAP complex. Ligation of LTβR recruits TRAF3 and TRAF2, with binding in the TRAF crevice, where NIK and cIAP also bind. LTβR competitively displaces NIK and cIAP, which halts the ubiquitinylation of NIK. F474 in TRAF3, and F410 in TRAF2 define the key binding sites for LTβR, NIK and cIAP. The specificity of the ubiquitin ligase is redirected to TRAF3 and TRAF2 when bound to the LTβR, forming a ubiquitin:TRAF E3 ligase that catalyzes polyubiquitination of TRAF2 and TRAF3. Consequentially, TRAF3 and TRAF2 are rapidly degraded depleting the cellular pools of TRAF3 and TRAF2, and allowing ligated LTβR to bind more TRAF3. Liberated NIK binds IKKα promoting p100 processing, essential for the formation of the RelB/p52 transcription complex

Inflammation and Autoimmunity

The functional role of LIGHT-HVEM in immune physiology has emerged as a potent activation signal for T cells. For instance, mice that constitutively expressed LIGHT in T cells developed a profound intestinal inflammation with expansion of activated T and B cells reminiscent of inflammatory bowel disease (IBD), an intestinal autoimmune condition with multigenic inheritance patterns. Recent identification of a genetic susceptibility locus for human inflammatory bowel disease at chromosome 19p13.3 revealed LIGHT as a candidate, although this chromosomal region is gene dense with several interesting candidates. Polymorphic variants in LIGHT impact in opposite fashion binding to LTβR and DcR3. These polymorphisms may represent natural selections in attempts to achieve balance between homeostasis and the inflammation and tissue damage needed for effective host defenses. These findings provide additional clues to the role of LIGHT in IBD.

Another distinct role for HVEM was revealed as an activator of an inhibitory cosignaling molecule, B T lymphocyte attenuator (BTLA). This finding represents the first example of a TNFR interacting with an Ig family member. HVEM appears to serve as a molecular switch between proinflammatory and inhibitory cosignaling for the activation of T cells.

Fig. 3 The LIGHT-HVEM-BTLA system. LIGHT is a positive regulator of HVEM signaling via TRAFs leading to activation of NFkB and AP1. HVEM activates inhibitory signaling by inducing tyrosine phosphorylation of the ITIM motif in BTLA. Decoy receptor-3 binds LIGHT inhibiting HVEM signaling; gD of herpes simplex virus binds HVEM blocking LIGHT and BTLA binding; UL144 of HCMV binds BTLA.

Immune Evasion Mechanisms

Herpesviruses are adept at modifying host immune responses. These pathogens persist in the host despite strong immune responses. The large DNA genomes of herpesviruses encode a variety of immune modulators, many of which have unknown functions. TNF signaling pathways regulate cell survival and death providing strong selective pressure for pathogens to evolve specific evasion mechanisms. Targeting members of the TNF/LT superfamily of cytokines is a strategy found in all herpesvirus, which suggests the existence of an intimate evolutionary link in their host-parasite relationship. We are interested in exploiting this evolutionary knowledge to learn how to control the immune system without causing immune suppression. Our recent studies indicate that evolutionary divergent herpesviruses target the LIGHT-HVEM-BTLA system (Fig. 3) providing strong evidence that this pathway is important for the T cell functions.

This intimate relationship between herpesvirus and the TNF-related cytokines led to the discovery of a novel mechanism of virus suppression by our laboratory. The experiments revealed the ability of LT-related cytokines to mediate a non-apoptotic block of viral replication that requires NFkB-dependent activation of interferon beta (IFNβ) gene expression. The dependence on virus and Lymphotoxin signaling to induce IFNb provides a molecular example of host-virus coexistence, which may in part account for the ability of CMV to establish a state of coexistence (détente), with its immunocompetent host. Our major goal is to use this knowledge to develop new approaches to the treatment of persistent virus infections.

Paper: Tumor Necrosis Factor Superfamily in Innate Immunity and Inflammation

Faculty Position in Immunology

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Showing 3 of 3

The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity.

Gommerman JL, Browning JL, Ware CF

Cytokine Growth Factor Rev 2014 Apr ;25(2):139-45

Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability.

Cheung TC, Coppieters K, Sanjo H, Oborne LM, Norris PS, Coddington A, Granger SW, Elewaut D, Ware CF

J Immunol 2010 Aug 1 ;185(3):1949-58

T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.

Cheung TC, Oborne LM, Steinberg MW, Macauley MG, Fukuyama S, Sanjo H, D’Souza C, Norris PS, Pfeffer K, Murphy KM, Kronenberg M, Spear PG, Ware CF

J Immunol 2009 Dec 1 ;183(11):7286-96

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Dr. Yu Xin (Will) Wang received his PhD at the University of Ottawa where he identified cellular asymmetry and polarity mechanisms regulating muscle stem cell self-renewal and skeletal muscle regeneration. He then carried out postdoctoral training at Stanford University School of Medicine developing single cell multi-omic approaches to characterize the regenerative process and what goes awry with disease and aging.

“I’ve always had a passion for science and became fascinated with how the body repairs and heals itself when I was introduced to the potential of stem cells in regenerative medicine. I was struck by the ability of a small pool of muscle stem cells that can rebuild and restore the function of muscle. My lab at Sanford Burnham Prebys aims to better understanding the repair process and harness our body’s ability to heal in order to combat chronic diseases and even counteract aging.”

Education and Training

Postdoctoral Fellowship, Stanford University School of Medicine
PhD in Cellular Molecular Medicine, University of Ottawa, Canada
BS in Biomedical Sciences, University of Ottawa, Canada

Prestigious Funding Awards

2020: NINDS K99/R00 Pathway to Independence Award

Honors and Recognition

Governor General’s Gold Medal – Canada

Related Disease
Aging-Related Diseases, Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease), Arthritis, Cachexia, Inflammatory/Autoimmune Disease, Multiple Sclerosis, Muscular Dystrophy, Myopathy, Neurodegenerative and Neuromuscular Diseases, Sarcopenia/Aging-Related Muscle Atrophy, Spinal Muscular Atrophy

Phenomena or Processes
Adult/Multipotent Stem Cells, Aging, Cell Signaling, Development and Differentiation, Epigenetics, Exercise, Extracellular Matrix, Neurogenesis, Organogenesis, Regenerative Biology, Transcriptional Regulation

Anatomical Systems and Sites
Immune System and Inflammation, Musculoskeletal System, Nervous System

Research Models
Clinical and Transitional Research, Computational Modeling, Human Adult/Somatic Stem Cells, Mouse

Techniques and Technologies
3D Image Analysis, Bioinformatics, Cellular and Molecular Imaging, Gene Knockout (Complete and Conditional), Genomics, High Content Imaging, High-Throughput/Robotic Screening, Live Cell Imaging, Machine Learning, Microscopy and Imaging, Proteomics, Transplantation

The Wang lab is interested in elucidating critical cell-cell interactions that mediate the function of tissue-specific stem cells during regeneration and disease, with a focus on

how a coordinated immune response can promote regeneration and
how autoimmunity impacts tissue function and hinder repair.

Specifically, the Wang lab aims to identify cellular and molecular crosstalk between muscle, nerve, and immune systems to develop targeted therapies that overcome autoimmune neuromuscular disorders and autoimmune aspects of “inflammaging.”

Yu Xin (Will) Wang’s Research Report

The lab’s research is translationally oriented and utilizes interdisciplinary molecular, genetic, computational (machine learning and neural networks), and bioengineering approaches to view biology and disease from new perspectives. We combine multi-omics sequencing and imaging methods to resolve how different cell types work together after injury to repair tissues and restore function. We use a data-driven approach to identify targetable disease mechanisms and, through collaborations with other researchers and clinicians, develop therapies that promote regeneration. Visit our lab website to learn more.

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Showing 3 of 3

Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength.

Palla AR, Ravichandran M, Wang YX, Alexandrova L, Yang AV, Kraft P, Holbrook CA, Schürch CM, Ho ATV, Blau HM

Science 2021 Jan 29 ;371(6528):

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Wang YX, Feige P, Brun CE, Hekmatnejad B, Dumont NA, Renaud JM, Faulkes S, Guindon DE, Rudnicki MA

Cell Stem Cell 2019 Mar 7 ;24(3):419-432.e6

Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division.

Dumont NA, Wang YX, von Maltzahn J, Pasut A, Bentzinger CF, Brun CE, Rudnicki MA

Nat Med 2015 Dec ;21(12):1455-63

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Related Disease
Aging-Related Diseases, Brain Cancer, Cancer, Childhood Diseases, Immune Disorders, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma

Phenomena or Processes
Adapter Proteins, Adult/Multipotent Stem Cells, Aging, Angiogenesis, Apoptosis and Cell Death, Bcl-2 Family, Cancer Biology, Cancer Epigenetics, Cell Adhesion and Migration, Cell Biology, Cell Cycle Progression, Cell Differentiation, Cell Motility, Cell Proliferation, Cell Signaling, Cell Surface Receptors, Cellular Senescence, Chromosome Dynamics, Combinatorial Therapies, Cytokines, Development and Differentiation, Disease Therapies, DNA Damage Checkpoint Function, Embryonic/Pluripotent Stem Cells, Epigenetics, Gene Regulation, Genomic Instability, Growth Factors, Hematopoiesis, Host Defense, Host-Pathogen Interactions, Inflammation, Innate Immunity, Kinase Inhibitors, Metastasis, Neurogenesis, Oncogenes, Phosphorylation, Posttranslational Modification, Receptor Tyrosine Kinases, Serine/Threonine Kinases, Signal Transduction, TNF-Family, Transcription Factors, Transcriptional Regulation, Tumor Microenvironment, Tumorigenesis, Tyrosine Kinases, Ubiquitin, Ubiquitin Protease System and Ubiquitin-like Proteins

Anatomical Systems and Sites
Brain, General Cell Biology, Hematopoietic System, Immune System and Inflammation, Nervous System

Research Models
Bacteria, Cultured Cell Lines, Human Adult/Somatic Stem Cells, Human Cell Lines, Mouse, Mouse Cell Lines, Mouse Embryonic Stem Cells, Mouse Somatic Stem Cells, Primary Cells, Primary Human Cells

Techniques and Technologies
3D Image Analysis, 3D Reconstructions, Biochemistry, Bioinformatics, Cell Biology, Cellular and Molecular Imaging, Chemical Biology, Computational Biology, Confocal Microscopy, Correlative Light and Electron Microscopy, Drug Delivery, Drug Discovery, Drug Efficacy, Electron Microscopy, Fluorescence Microscopy, Fragment-Based Drug Design, Gene Expression, Gene Knockout (Complete and Conditional), Gene Silencing, Genetics, Genomics, High Content Imaging, High-Throughput/Robotic Screening, In vivo Modeling, Live Cell Imaging, Live Imaging, Mass Spectrometry, Microscopy and Imaging, Molecular Biology, Molecular Genetics, Nucleic Acid Synthesis, Protein-Protein Interactions, Protein-Small Molecule Interactions, Proteomics, Rational Drug Design, RNA Interference (RNAi), Scanning Cytometry, Small Molecule Compounds, Transgenic Organisms, Transplantation

We seek to understand why cancer occurs and what is the Achille’s heel of cancer, and to develop effective therapeutic interventions.

The successful treatment of any disease requires a good understanding of the mechanisms at work. Cancer is fundamentally caused by aberrant gene expression, which reflects the misinterpretation of DNA information at both genetic and epigenetic levels. We are interested in uncovering DNA-related alterations that drive cancer-favored transcriptional programs, identifying cancer-specific vulnerabilities, and developing effective therapeutic interventions for cancer treatment.

Xueqin Sun’s Research Report

Precise gene expression (the interpretation of DNA) is essential for almost all biological processes, and understanding gene regulation is one of the most pivotal frontiers in biological research under both health and disease circumstances. Gene expression is mainly regulated at genetic (with changes of DNA sequence) and epigenetic (without changing DNA sequence) levels. And gene dysregulation can lead to various health conditions and diseases, including developmental disorders, aging, and cancer. The overarching goal of Sun Lab is to uncover driving genetic and epigenetic alterations involved in cancer, to understand how developmental pathways and aging process impact cancer progression, and to identify mechanisms of action for developing more effective therapeutic strategies.

We are an interdisciplinary lab particularly focused on the following research directions:

The EP400 chromatin remodeling complex
The EP400 complex is an evolutionarily conserved SWR1-class ATP-dependent chromatin remodeling complex encompassing ~17 components, with a total molecular mass of ~1.5 mega-dalton. The EP400 complex plays critical roles in diverse cellular processes, including chromosome stability, transcription, DNA recombination, DNA damage repair, embryonic stem cell renewal/development, and oncogenesis. The EP400 complex can incorporate histone variants, such as H2AZ and H3.3, into the genome to regulate gene expression. Our recent work discovers BRD8—one of the core subunits of the EP400 complex—as a unique vulnerability of p53 wildtype glioblastoma (GBM), the most prevalent and devastating type of brain cancer. BRD8-driven EP400 complex highjacks H2AZ at p53 target loci to block p53-mediated transactivation and tumor suppression (Nature, 2023). The bromodomain of BRD8 plays the key role in this process. Bromodomain is a druggable domain as evidenced by a number of successful small molecules targeting diverse bromodomains encoded by the human genome across multiple cancer types. Furthermore, findings from others and us suggest that the EP400 complex is involved in different cancers. Thus, we seek to unravel the roles of the EP400 complex in health and disease, and to better understand how to target the EP400 complex for developing effective therapeutic interventions.
The NuRD chromatin remodeling complex
The NuRD complex is also a highly conserved class of ~ 1 MDa multi-subunit chromatin remodeling complexes that consume energy derived from ATP hydrolysis to remodel the configuration of chromatin to control gene transcription programs, with a primary role in gene silencing. Chromatin remodeling is vital for efficiently framing the cellular response to both intrinsic and extrinsic signals and has enormous implications for determining cellular states. NuRD complex is unique in combining ATP-dependent chromatin remodeling, protein deacetylase activity, and recognition of methylated DNA and histone modifications, and has multifarious roles in chromatin organization, transcription regulation, and genome maintenance; thereby, largely impacts health and disease. The NuRD complex has been in the central stage of brain development studies, and is significantly related to brain disorders/diseases. Interestingly, NuRD complex re-assembles by exchanging the chromatin remodeling subunits CHD3/4/5 to achieve specific regulation of an array of genes required for generating distinct cell types in a highly organized manner, especially over brain development. Amongst the genes encoding NuRD complex components, CHD5 is located in human chromosome 1 short arm (1p36), a region that is frequently hemizygously deleted in diverse cancers. Besides genetic deletion, CHD5 is also often silenced in cancer cells due to epigenetic mechanisms, such as promoter hypermethylation, aberrant expression of other chromatin regulators, and microRNAs-mediated translational repression and/or mRNA instability. Our current work seeks to determine whether and how CHD5-driven NuRD complex is involved in tumorigenesis (In preparation, 2024). We will further understand how NuRD complex is involved in both development and tumorigenesis, and identify mechanism of action to develop rational therapeutic strategies.
Novel genetic and epigenetic underpinnings in GBM
GBM is notorious for being a highly complex and plastic cancer type. However, at the genetic level, GBM harbors a relatively low genetic alteration burden compared to the majority of other cancers from pan-cancer profiling studies. This indicates the largely undocumented epigenetic mechanisms that interplay with genetic alterations and co-reprogram transcriptional networks essential for GBM development. Epigenetic changes are usually reversible by nature, as evidenced by numerous successes in targeting epigenetic regulators using small chemical compounds. As actionable therapeutic targets for GBM have been scarce, we are keen to uncover novel epigenetic pathways underlying gliomagenesis under different genetic backgrounds, which will potentially provide promising therapeutic opportunities for GBM treatment.
Novel GBM mouse models
Despite decades of effort, our knowledge about GBM biology is still very limited. GBM harbors a number of genetic alterations. However, among these recurrent genetic lesions, only several have been implicated in gliomagenesis, with most being undocumented. Moreover, the mechanisms by which these genetic alterations are involved in establishing GBM-favored epigenetic landscapes and transcription programs during GBM progression are still largely elusive. The lack of efficient approach to establish mouse models for investigating gene function in gliomagenesis and the limit of current mouse models to recapitulate clinical GBM features in brain is the prime reason that hinders GBM biological research. To this end, we have developed an engineered neural stem cells (NSCs)-based strategy to rapidly generate highly aggressive GBM with desired genetic lesions (genotypes) in mouse brain. Therefore, we will further optimize this strategy to establish a series of novel mouse models possessing recurrent combinations of genetic alterations (genotypes) in GBM, in order to systematically study whether and how these genetic lesions are involved in gliomagenesis and identify genotype-specific dependencies.
Crosstalk between GBM cells and tumor microenvironment
GBM exhibits highly diffuse and infiltrative nature, which contributes to therapeutic resistance and tumor relapse after surgical removal, resulting in dismal prognosis. A better understanding of gliomagenesis involving not only malignant cells themselves, but also the holistic bidirectional interactions of malignant cells with a variety of proximal and distal cells within the organism, is profound for developing novel effective therapies to improve GBM prognosis. Individual invasive GBM cells intermingle with normal brain cells and often cause relapse in brain areas essential for patient survival. Emerging evidence indicates that glioma cells highjack normal brain cells to thrive, and even transform them. However, how gliomagenesis reshapes ecological composition/landscape in host brain and how brain microenvironment affects gliomagenesis are still largely unclear. By using our novel highly invasive mouse models that recapitulate the multiforme diffuse topographies of GBM in brain, we seek to understand the interactions between GBM cells and brain microenvironment, and identify extrinsic pathways that are essential for GBM progression and migration.

Our lab is focused on both fundamental questions in cancer biology and translation of promising therapeutic strategies.

To achieve these, we work together with many fantastic collaborators to develop and leverage cutting-edge technologies, including but not limited to, high-throughput functional genomics (CRISPR/Cas9 screens, exon tiling scan, targeted mutagenesis, etc.), cell and molecular biology, genomics, epigenomics, proteomics, biochemistry, microscopy (2D/3D, time-lapse, two-photon, light sheet, etc.), automated large-scale drug synthesis/screening, structural biology, single cell and spatial multi-omics, artificial intelligence, and bioinformatics. We also establish novel patient-derived models and novel mouse models to facilitate our research programs. Our ultimate goals are to better understand fundamental genetic and epigenetic apparatuses involved in cancer-specific transcriptional networks, provide more effective therapeutic opportunities, and contribute to shifting the paradigms in cancer treatment and precision medicine.

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Showing 3 of 3

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Sun X, Klingbeil O, Lu B, Wu C, Ballon C, Ouyang M, Wu XS, Jin Y, Hwangbo Y, Huang YH, Somerville TDD, Chang K, Park J, Chung T, Lyons SK, Shi J, Vogel H, Schulder M, Vakoc CR, Mills AA

Nature 2023 Jan ;613(7942):195-202

ANP32A regulates histone H3 acetylation and promotes leukemogenesis.

Yang X, Lu B, Sun X, Han C, Fu C, Xu K, Wang M, Li D, Chen Z, Opal P, Wen Q, Crispino JD, Wang QF, Huang Z

Leukemia 2018 Jul ;32(7):1587-1597

Induction of INKIT by Viral Infection Negatively Regulates Antiviral Responses through Inhibiting Phosphorylation of p65 and IRF3.

Lu B, Ren Y, Sun X, Han C, Wang H, Chen Y, Peng Q, Cheng Y, Cheng X, Zhu Q, Li W, Li HL, Du HN, Zhong B, Huang Z

Cell Host Microbe 2017 Jul 12 ;22(1):86-98.e4

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Jamey Marth is a Professor at Sanford Burnham Prebys. He has also been Director of the Center for Nanomedicine at the University of California Santa Barbara and Professor in the Department of Molecular, Cellular, and Developmental Biology. Dr. Marth received a PhD degree in Pharmacology from the University of Washington where he trained in the laboratories of Roger M. Perlmutter and Edwin G. Krebs. Dr. Marth’s previous positions included Professor of Medical Genetics at the Biomedical Research Center, University of British Columbia; Professor of Cellular and Molecular Medicine at the University of California San Diego; and Investigator of the Howard Hughes Medical Institute.

Education

1987: PhD, University of Washington, Pharmacology
1984: BS, University of Oregon, Genetics and Chemistry

Honors and Recognition

2017: Karl Meyer Award, Society for Glycobiology
2009-2020: John Carbon Chair in Biochemistry and Molecular Biology
2009-2019: Duncan and Suzanne Mellichamp Chair in Systems Biology
2009: Julius Stone Lectureship Award: Society for Investigative Dermatology
1995-2009: Investigator Award, Howard Hughes Medical Institute
1991-1995: Faculty Scholarship, The Medical Research Council of Canada

Related Disease
Cancer, Colitis, Diabetes – General, Inflammatory/Autoimmune Disease, Sepsis

I am a molecular and cellular biologist specializing in diseases attributable to protein glycosylation. My education and training span molecular genetics, biochemistry, pharmacology, cell biology, immunology, hematology, developmental biology, microbiology, and glycobiology.

As an enzymatic process essential to cells, glycosylation produces saccharides linked by glycosidic bonds to proteins, lipids, and themselves, termed glycans. The vast majority of secreted and cell surface proteins are post-translationally modified by glycosylation during transit through the secretory pathway, termed glycoproteins. A widely used college level cell biology textbook authored by others includes glycans as one of the four main families of the organic molecules of all cells, with lipids, proteins, and nucleic acids and that together they compose the macromolecules and other assemblies of the cell. The structures of glycans (and lipids) are, however, synthesized by template-independent processes, rendering them hard to predict and study. Cells produce and regulate an abundant and diverse glycome of glycosidic linkages in which some of the biological information is decoded by one or more glycan-binding receptors, termed lectins.

Glycans and lectins represent a significant percentage of genes in the genomes of organisms, with several hundred present in mammals. Because glycan biosynthesis, diversification, and degradation rely upon corresponding gene and enzyme function, glycan function can be investigated similarly to other enzymatic and metabolic pathways, such protein phosphorylation. However, we and others found that intact organisms were typically required to discover the functions of protein glycosylation in mammals. My laboratory has focused on discovering the biological information contained within select glycosidic linkages of N- and O-glycans in determining the function and fate of discrete glycoproteins that further contribute to the pathogenesis of autoimmune disease, colitis, diabetes, and sepsis.

To understand the nature and extent of the information generated by glycosidic linkages, we have applied multiple molecular approaches to investigate protein glycosylation in mice and humans. In doing so, we have contributed to the development of enabling technologies with broad applicability, such as conditional mutagenesis by Cre-lox recombination in living animals to determine gene function with temporal and spatial selectivity. My laboratory also develops and studies experimental systems that may better represent real-world models of environmental factors that trigger acquired and common human diseases, results from which have been consistent with clinical findings of human patients. My laboratory includes interdisciplinary team-based collaborations that integrate expertise in immunology, infectious disease, hematology, and more recently, cancer, and is especially focused upon glycosidic linkages attached to the N- and O-glycans of glycoproteins.

The physiological systems regulated by protein glycosylation are broad even when comparing among sequential biosynthetic steps, and our findings continue to indicate the presence of undiscovered information of medical relevance residing in the glycan linkages of glycoproteins.

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Showing 3 of 3

Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.

Ohtsubo K, Chen MZ, Olefsky JM, Marth JD

Nat Med 2011 Aug 14 ;17(9):1067-75

Recurrent infection progressively disables host protection against intestinal inflammation.

Yang WH, Heithoff DM, Aziz PV, Sperandio M, Nizet V, Mahan MJ, Marth JD

Science 2017 Dec 22 ;358(6370):

Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis.

Yang WH, Heithoff DM, Aziz PV, Haslund-Gourley B, Westman JS, Narisawa S, Pinkerton AB, Millán JL, Nizet V, Mahan MJ, Marth JD

Cell Host Microbe 2018 Oct 10 ;24(4):500-513.e5

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Dr. Blaho began her research career focused on how bioactive lipids contribute to the innate immune response against bacterial infection, characterizing roles for eicosanoids in the generation and resolution of Lyme arthritis pathology. The wild diversity of lipid species led Dr. Blaho to Weill Cornell Medical College in New York City to pursue postdoctoral training in the field of sphingolipids, particularly sphingosine 1-phosphate (S1P), and its receptors. Advancing to Instructor at Weill Cornell and later, Research Assistant Professor at Sanford Burnham Prebys, Dr. Blaho continued her research in lipid chaperones and receptor signaling, with an emphasis on cell-type differential effects on hematopoiesis and immunity in response to cell stressors. In August of 2019, Dr. Blaho joined the faculty at the Institute as an Assistant Professor in the Immunity and Pathogenesis program.

Why do you do what you do?

The immune system has the power to protect us from invading pathogens and cancer or to initiate a “self-destruct” sequence that consumes us with inflammation and autoimmunity. It is fascinating to me that a simple ubiquitous fat molecule like S1P can control the birth and destiny of immune cells.

Education

2014-2016: Instructor, Weill Cornell Medicine, Pathology and Laboratory Medicine and Neuroscience
2009-2014: Post-doctoral training, Weill Cornell Medicine, Pathology and Laboratory Medicine
2007-2009: Post-doctoral training, University of Missouri, Columbia, Veterinary Pathobiology
2007: PhD, University of Missouri, Columbia, Molecular Microbiology and Immunology – BS

Funding Awards and Collaborative Grants

National Heart, Lung, and Blood Institute R01
American Heart Association Scientist Development Grant
2014-15: Leon Levy Neuroscience Foundation Grant
2015: Foundation LeDucq SphingoNet Young Investigator Grant
2009-12: National Cancer Institute Individual Ruth L. Kirschstein Post-doctoral Fellowship

Honors and Recognition

2017: British Journal of Pharmacology Lecture: FASEB Summer Research Conference on Lysophospholipids and Related Mediators – from bench to clinic.
2014: Leon Levy Foundation Neuroscience Fellow
2010: Keystone Scholarship, Bioactive Lipids: Biochemistry and Diseases
2008: Keystone Scholarship, Eicosanoids and Other Mediators of Chronic Inflammation
2007: Young Investigator Award in Inflammation, Eicosanoid Research Foundation
2004: National Academy of Sciences Christine Mirzayan Policy Fellow, Institute of Medicine Board on Health Sciences Policy

Related Disease
Biochemistry, Immune Disorders, Inflammatory/Autoimmune Disease, Leukemia/Lymphoma, Molecular Biology, Multiple Sclerosis

Phenomena or Processes
Adaptive Immunity, Apoptosis and Cell Death, Cell Signaling, G-Protein Coupled Receptors, Hematopoiesis, Inflammation, Innate Immunity

Anatomical Systems and Sites
Hematopoietic System, Immune System and Inflammation, Vasculature

Research Models
Human Adult/Somatic Stem Cells, Mouse, Mouse Somatic Stem Cells, Primary Cells

Techniques and Technologies
Cell Biology, Cellular and Molecular Imaging, Confocal Microscopy, Fluorescence Microscopy, Gene Expression, Lipid Bilayers, Mass Spectrometry

The lipid sphingosine 1 phosphate (S1P) is found in high levels in the blood and lymph and is primarily carried by the protein ApoM, found on HDL. S1P can affect the cardiovascular, nervous, and immune systems via interaction with cell surface-expressed receptors, S1P1-5. My work is determining how changing S1P carrier or receptor expression and signaling can affect cells of the immune system, particularly in the bone marrow, and how this alters their ability to respond to stress or infection.

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Showing 3 of 3

HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.

Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL, Steinman L, Han MH, Hla T

Nature 2015 Jul 16 ;523(7560):342-6

HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.

Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, Dahlbäck B, Kono M, Proia RL, Smith JD, Hla T

Sci Signal 2015 Aug 11 ;8(389):ra79

An update on the biology of sphingosine 1-phosphate receptors.

Blaho VA, Hla T

J Lipid Res 2014 Aug ;55(8):1596-608

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Biography

Research

Select Publications

IFN-β Selectively Inhibits IL-2 Production through CREM-Mediated Chromatin Remodeling.

IRF7-dependent IFN-β production in response to RANKL promotes medullary thymic epithelial cell development.

T cell-intrinsic and -extrinsic contributions of the IFNAR/STAT1-axis to thymocyte survival.

Biography

Education

Other Appointments

Honors and Recognition

Research

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SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML.

FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.

Emerging principles in protease-based drug discovery.

Biography

Education

Funding Awards and Collaborative Grants

Honors and Recognition

Research

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Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy.

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer’s disease.

Biography

Research

Biography

Research

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The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity.

Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailability.

T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.

Biography

Education and Training

Prestigious Funding Awards

Honors and Recognition

Research

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Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division.

Research

Xueqin Sun’s Research Report

Select Publications

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

ANP32A regulates histone H3 acetylation and promotes leukemogenesis.

Induction of INKIT by Viral Infection Negatively Regulates Antiviral Responses through Inhibiting Phosphorylation of p65 and IRF3.

Biography

Education

Honors and Recognition

Research

Select Publications

Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.

Recurrent infection progressively disables host protection against intestinal inflammation.

Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis.

Biography

Why do you do what you do?

Education

Funding Awards and Collaborative Grants

Honors and Recognition

Research

Select Publications

HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.

HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.

An update on the biology of sphingosine 1-phosphate receptors.