Dr. Sheffler joined Sanford Burnham Prebys in September 2012.
2005-2010: Post-doctoral Training, Vanderbilt University, Nashville, TN Mentor: Jeffrey Conn, PhD
1999-2005: PhD, Case Western Reserve University, Cleveland, OH Mentor: Bryan Roth, MD, PhD
2013 NARSAD Young Investigator Award Brain and Behavior Research Foundation
Related Disease
Alzheimer’s Disease, Huntington’s Disease, Neurodegenerative and Neuromuscular Diseases, Neurological and Psychiatric Disorders, Schizophrenia
Dr. Sheffler joined the Sanford Burnham Prebys faculty in September 2012. Prior to this, he was a Research Assistant Professor at Vanderbilt University in the laboratory of P. Jeffrey Conn (2010-2012), where he also performed post-doctoral work (2006-2010). Dr. Sheffler has over 15 years’ experience in the study of G-protein coupled receptor (GPCR) signaling, assay development, high throughput screening for novel GPCR ligands, cell biology, neuroscience, and pharmacology. His interests are in the complex regulation of GPCRs: their signal transduction, ligand binding, receptor desensitization, and the processes of GPCR internalization and down-regulation. In addition, he has also has a specific interest in both the pharmacology of GPCRs, in general mechanisms of signal transduction, and in the pathogenesis of schizophrenia. During his graduate studies at Case Western Reserve University in the laboratory of Bryan L. Roth, MD, PhD, he discovered the regulation of 5-HT2A serotonin receptor signal transduction by p90 ribosomal S6 kinase (RSK2). During his post-doctoral studies and work as a Research Assistant Professor at Vanderbilt University, he focused on the discovery and characterization of orthosteric and allosteric modulators of GPCRs and led pharmacology efforts characterizing novel M1 muscarinic acetylcholine receptor agonists and antagonists, M1 positive allosteric modulators (PAMs), Glycine Transporter Type 1 (GlyT1) inhibitors, and novel Group II metabotropic glutamate receptor (mGlu) PAMs and NAMs. Dr. Sheffler’s research has resulted in more than 45 journal articles and is a listed inventor on five patent applications pertaining to small molecule therapeutics. Dr. Sheffler received a NARSAD Young Investigator Award in 2013 from the Brain and Behavior Research Foundation.
The metabotropic glutamate receptors (mGlus) are G protein-coupled receptors (GPCRs) that play numerous roles in modulating synaptic transmission and cell excitability. Recent preclinical and clinical studies provide strong evidence that agonists of the group II mGlus, comprised of the mGlu2 and mGlu3 subtypes, may provide a novel approach to treatment of schizophrenia and anxiety disorders. Based on this, there has been a major focus on understanding the roles of these receptors in regulating transmission in forebrain and limbic circuits. However, currently available orthosteric (glutamate site) agonists activate both mGlu2 and mGlu3 and do not provide insight into which subtype is most important for clinical efficacy. Alternatively, recent focus on compounds interacting with less highly conserved allosteric sites has led to advances in subtype selective compound development. Dr. Sheffler and others have discovered and characterized highly selective mGlu2 positive allosteric modulators (PAMs), that have no effect on mGlu3, and these compounds have allowed us to elucidate many of the physiological roles of mGlu2. These PAMs do not activate the receptor directly but act allosterically to potentiate glutamate responses. Dr. Sheffler and collaborators have also discovered group II mGlu negative allosteric modulators (NAMs) and have very recently discovered the first highly selective antagonist of mGlu3. The development of these pharmacological tools provides an opportunity to fully elucidate the roles of these mGlu subtypes. The group II mGlus play important roles in regulating transmission through the hippocampal formation. For example, activation of presynaptic group II mGlus reduces transmission at numerous hippocampal synapses including perforant path-dentate gyrus synapses and the mossy fiber synapse. In contrast, presynaptic group II mGlus are not involved in directly regulating transmission at the Schaffer collateral – CA1 (SC-CA1) synapse. However, we have previously reported extensive studies demonstrating group II mGlu involvement in a novel form of glial-neuronal communication in hippocampal area CA1. When coincidentally activated with β-adrenergic receptors (βARs) in astrocytes, group II mGlus induce a marked potentiation of cAMP responses elicited by activation of βARs. This synergistic increase in glial cAMP accumulation results in the release of adenosine, which activates presynaptic A1 adenosine receptors on neighboring SC terminals and induces a profound depression of transmission at the SC-CA1 synapse. This novel form of glial-neuronal signaling may provide a protective mechanism to reduce the risk of excitotoxicity when there is excessive excitatory drive to the hippocampus, such as during periods of intense or prolonged stress. This potential role has implications relevant for the therapeutic effects of group II mGlu agonists and is consistent with multiple studies suggesting group II mGlu agonists can reduce both acute and long term responses to stress. We have postulated that this effect is mediated by mGlu3 based on heavy expression of mGlu3 in hippocampal astrocytes. However, until now, selective reagents that differentiate between mGlu2 and mGlu3 have not been available to rigorously determine the specific group II mGlu subtype involved. The long term goal of Dr. Sheffler’s research is to establish the relative roles of individual group II mGlu subtypes in mediating glial-neuronal communication and modulating synaptic transmission in the hippocampus using pharmacological, biochemical, and electrophysiological approaches.
Dhanya RP, Sheffler DJ, Dahl R, Davis M, Lee PS, Yang L, Nickols HH, Cho HP, Smith LH, D’Souza MS, Conn PJ, Der-Avakian A, Markou A, Cosford ND
J Med Chem 2014 May 22 ;57(10):4154-72Sheffler DJ, Nedelcovych MT, Williams R, Turner SC, Duerk BB, Robbins MR, Jadhav SB, Niswender CM, Jones CK, Conn PJ, Daniels RN, Lindsley CW
Bioorg Med Chem Lett 2014 Feb 15 ;24(4):1062-6Jones CK, Sheffler DJ, Williams R, Jadhav SB, Felts AS, Morrison RD, Niswender CM, Daniels JS, Conn PJ, Lindsley CW
Bioorg Med Chem Lett 2014 Feb 15 ;24(4):1067-70Dr. Zhao joins us from University of California San Francisco, where he recently completed his Postdoctoral Training. His lab will focus on understanding how proteins function under different physiological and disease states from a structural biology perspective. Specifically, Dr. Zhao brings significant expertise in visualizing proteins at high resolution using cryogenic electron microscopy (cryo-EM). Dr. Zhao received his Bachelor’s and PhD in Medical Biophysics from the University of Toronto, Canada, where he completed 5 years of graduate training investigating rotary ATPases. He then went on and completed 5 years of postdoctoral training at UCSF studying Transient Receptor Potential ion channels.
2010: Postdoctoral associate, Molecular Biophysics and Biochemistry, Yale University
2009: PhD, Computer Science, Yale University
2003: M.Phil., Computer Science, The University of Hong Kong
1999: B.Eng., Computer Engineering, The University of Hong Kong
Related Disease
Biliary Atresia, Cancer, Diabetes – General, Hirschsprung Disease, Liver Cancer, Nasopharyngeal Carcinoma, Type 2 Diabetes
Phenomena or Processes
Cancer Epigenetics, Gene Regulation, Oncogenes, Posttranslational Modification, Transcriptional Regulation, Tumor Microenvironment
Anatomical Systems and Sites
Endocrine System, General Cell Biology, Immune System and Inflammation, Liver
Research Models
Computational Modeling
Techniques and Technologies
Bioinformatics, Comparative Genomics, Genomics, Machine Learning, Protein-Protein Interactions, Systems Biology
We study gene regulatory mechanisms by means of computational modeling. To facilitate our data-centric approach, we develop novel methods for analyzing large amounts of biological data, including those produced by cutting-edge high-throughput experiments. Our computational models provide a systematic way to investigate the functional effects of different types of perturbations to regulatory mechanisms, which creates testable hypotheses for studying human diseases and facilitates translational research.
YouTube: Bioinformatics micro-modules
ENCODE Project Consortium
Nature 2012 Sep 6 ;489(7414):57-74Gerstein MB, Lu ZJ, Van Nostrand EL, Cheng C, Arshinoff BI, Liu T, Yip KY, Robilotto R, Rechtsteiner A, Ikegami K, Alves P, Chateigner A, Perry M, Morris M, Auerbach RK, Feng X, Leng J, Vielle A, Niu W, Rhrissorrakrai K, Agarwal A, Alexander RP, Barber G, Brdlik CM, Brennan J, Brouillet JJ, Carr A, Cheung MS, Clawson H, Contrino S, Dannenberg LO, Dernburg AF, Desai A, Dick L, Dosé AC, Du J, Egelhofer T, Ercan S, Euskirchen G, Ewing B, Feingold EA, Gassmann R, Good PJ, Green P, Gullier F, Gutwein M, Guyer MS, Habegger L, Han T, Henikoff JG, Henz SR, Hinrichs A, Holster H, Hyman T, Iniguez AL, Janette J, Jensen M, Kato M, Kent WJ, Kephart E, Khivansara V, Khurana E, Kim JK, Kolasinska-Zwierz P, Lai EC, Latorre I, Leahey A, Lewis S, Lloyd P, Lochovsky L, Lowdon RF, Lubling Y, Lyne R, MacCoss M, Mackowiak SD, Mangone M, McKay S, Mecenas D, Merrihew G, Miller DM 3rd, Muroyama A, Murray JI, Ooi SL, Pham H, Phippen T, Preston EA, Rajewsky N, Rätsch G, Rosenbaum H, Rozowsky J, Rutherford K, Ruzanov P, Sarov M, Sasidharan R, Sboner A, Scheid P, Segal E, Shin H, Shou C, Slack FJ, Slightam C, Smith R, Spencer WC, Stinson EO, Taing S, Takasaki T, Vafeados D, Voronina K, Wang G, Washington NL, Whittle CM, Wu B, Yan KK, Zeller G, Zha Z, Zhong M, Zhou X, modENCODE Consortium, Ahringer J, Strome S, Gunsalus KC, Micklem G, Liu XS, Reinke V, Kim SK, Hillier LW, Henikoff S, Piano F, Snyder M, Stein L, Lieb JD, Waterston RH
Science 2010 Dec 24 ;330(6012):1775-87Cao Q, Anyansi C, Hu X, Xu L, Xiong L, Tang W, Mok MTS, Cheng C, Fan X, Gerstein M, Cheng ASL, Yip KY
Nat Genet 2017 Oct ;49(10):1428-1436Yu Yamaguchi earned his MD from Tohoku University in Japan in 1981, followed by a PhD in 1985, and training in obstetrics and gynecology at the same institute. Dr. Yamaguchi came to Sanford Burnham Prebys for his postdoctoral training. He was appointed to the staff in 1991.
The Humanitarian Scientific Achievement Award, The MHE Research Foundation
The Kushima Prize, The Alumni Association, Tohoku University School of Medicine
Member, Scientific and Medical Advisory Board, The MHE Research Foundation
Related Disease
Alzheimer’s Disease, Arthritis, Autism Spectrum Disorders, Bone Mineralization Disorders, Epilepsy, Multiple Hereditary Exostoses
The goal of research in the Yamaguchi laboratory is to understand the role of proteoglycans and glycosaminoglycans in the context of development and human disorders. The general strategy is to define the role of proteoglycans and glycosaminoglycans by characterizing the phenotype of mutant mice lacking the synthesis of individual glycosaminoglycans. Specifically, mutant mice lacking the Ext1 and Has genes have been created to study heparan sulfate and hyaluronan, respectively. Recent progress in genetic studies in humans and mice has begun to reveal that deficiencies in glycosaminoglycans can be the causes and/or confounding factors of human childhood disorders. The Yamaguchi lab is now working to clarify the molecular mechanisms of two such disorders (multiple hereditary exostoses and autism) in order to develop new medical treatments.
For more information on the impact of Dr. Yamaguchi’s work, read letters from the patients with MHE.
Proteoglycans are a family of glycoproteins consisting of a core protein and a various number of long sugar chains called glycosaminoglycans attached to the core protein (Fig. 1). There are four classes of glycosaminoglycans; heparan sulfate, chondroitin sulfate, keratan sulfate, and hyaluronan (hyaluronic acid). Heparin, the anticoagulant widely used in clinics, is a specialized form of heparan sulfate. Although there is ample circumstantial evidence that these glycosaminoglycans have important biological functions, a complete understanding of their function and their relevance to human diseases requires genetic animal models.
Figure 1. Proteoglycans consist of a protein core and one or more covalently attached glycosaminoglycan chains. From Esko, JD, Kimata, K., and Lindahl, U. Proteoglycans and Sulfated Glycosaminoglycans, In: Essentials of Glycobiology, CSH Press.
HEPARAN SULFATE – The Ext1 gene encodes an enzyme essential for the elongation of nascent heparan sulfate chains. As a result of genetic ablation of Ext1 using a ‘conditional knockout’ approach, heparan sulfate is eliminated from specific tissues and cell types. Our previous studies using brain-specific Ext1 conditional knockout have demonstrated critical roles of heparan sulfate in brain patterning, neurogenesis in the cerebral cortex, and pathfinding of various axon tracts (1)(2)(3)(4). More recently, conditional Ext1 knockout in developing limb bones revealed critical roles of heparan sulfate in the growth and patterning of bones and joint formation (5).
Moreover, our conditional Ext1 mutant mouse model has been distributed to more than 20 laboratories worldwide to characterize the role of heparan sulfate in various tissues and cell types, such as colon (6), kidney (7), lymphocytes (8), blood vessels (9), eyes (10), embryonic stem cells (11), and so on.
HYALURONAN – Three Has genes (Has1, Has2, Has3) encode the entire repertoire of hyaluronan synthases in mammalian cells. Genetic ablation of these genes, singly or in combination, results in a reduction or total elimination of hyaluronan, depending on the repertoire of Has expression in the given tissue. We created a conditional null allele of the Has2 gene, which is the predominant Has in many tissues. Our conditional Has2 knockout study targeted to the limb bud mesenchyme has revealed that hyaluronan plays a critical role in the proliferation and maturation of chondrocytes in the developing limb skeleton (12). Like Ext1 mutant mice, these Has2 conditional knockout mice are being used in more than a dozen laboratories worldwide for studies on the role of hyaluronan in various tissue and cell types.
Deficiencies in glycosaminoglycan synthesis can be the causes of childhood disorders
Recent progress in genetic studies in humans and mice has begun to reveal that deficiencies in glycosaminoglycans can be the causes and/or confounding factors of human childhood disorders. The research focus of our lab is to elucidate the molecular mechanisms of such disorders and to develop new medical treatments. We are currently studying two such disorders.
MULTIPLE HEREDITARY EXOSTOSES – One of the major diseases studied in our lab is Multiple Hereditary Exostoses (MHE; also known as Hereditary Multiple Exostoses [HME] or Multiple Osteochondroma [MO]). MHE is caused by a mutation in Ext1 (see above) or its related gene, Ext2. As mentioned above, these genes encode an enzyme necessary to produce heparan sulfate. MHE occurs in children of 0-12 years old. Although no comprehensive survey has been conducted, it is estimated that there are several thousand individuals affected by MHE in the US, which makes MHE one of the more prevalent among ’rare diseases’. Dr. Yamaguchi is a member of the scientific advisory board of the MHE Research Foundation and has been working to promote collaborations between basic scientists, academic physicians, and patient advocates.
Children with MHE suffer from the formation of multiple –– sometimes as many as 100 –– bony tumors (osteochondromas) (Fig. 2). These bony tumors stunt their growth and can cause pain and disfigurement. Fortunately, the chance these tumors becomes cancerous is relatively low, partly because they are surgically removed as they develop. This means, however, children with MHE need to go through multiple surgeries over the course of their lives. There is currently no medical treatment for the disease.
Figure 2. MHE patients, Carol and her 12-year-old son, Bruce. Shown on the right are three-dimensional CT images of Bruce’s right upper leg and knee joint area. Note that there are many bony protrusions (‘exostoses’), as indicated by white arrowheads. These tumors need to be surgically removed to prevent possible malignant transformation. Surgery is also needed to correct bone deformities and bone length inequalities. For example, Bruce and Carol have had 21 and 36 surgeries, respectively.
Our lab is currently working to elucidate the molecular and cellular mechanisms of MHE. One of the major thrusts has been to create a mouse model that mimics the manifestations of human MHE. A long-term issue of MHE research has been the lack of mouse models that faithfully recapitulate the manifestation of human MHE; when Ext genes were inactivated in mice just as they are in human MHE patients, the mice failed to develop the symptoms of MHE. Instead of knocking out the Ext1 gene in the whole mouse, we targeted the gene in only a small fraction of bone cells (Ext1-SKO mice). This minimalistic approach led to a mouse with all the physical manifestations of MHE, such as bony protrusions, short stature, and other skeletal deformities (Fig. 3)(13). The new mouse model answered some long-standing questions about MHE. Scientists had gone back and forth on whether osteochondromas observed in MHE are true tumors or just malformations of the bone. In this study, the tumors were made up of two cell types. A minority were mutant cells lacking Ext1, but, amazingly, most were normal bone cells. Hence, osteochondroma in MHE is not considered a true neoplasm in its strictest sense.
Figure 3. Ext1-SKO mice develop multiple osteochodromas in a pattern almost identical to human MHE. The X-ray images of the knee joint area of an MHE patient and the wrist, knee, and shoulder areas of Ext1-SKO mice. Osteochondromas are indicated by arrows. Ext1-SKO mice also mimic other skeletal deformities frequently seen human MHE, such as bowing of the forearm, the subluxation/dislocation of the radial head, and scoliosis (not shown).
Our lab has been using this and additional mouse models to further dissect the pathogenic mechanism of MHE. Moreover, this mouse model provides new opportunities to test potential drugs to prevent osteochondroma formation and other clinical symptoms of MHE.
AUTISM – Children with MHE sometimes suffer from neurological and mental symptoms, which is not surprising because heparan sulfate is expressed and plays critical roles in the nervous system (1). The MHE community has long noticed the prevalence of autism-like behavioral traits in the patient population, and there are clinical reports describing the association of autism with MHE. Aided by the funds from the Sanford Health and the MHE Research Foundation, we have been studying the behavior of Ext1 mutant mice. Our preliminary data suggest that heparan sulfate has indeed a physiological function in the nervous system, and that its deficiency can cause behavioral deficits relevant to human autism. We are also analyzing DNA samples from individuals with autism for abnormalities in enzymes for heparan sulfate synthesis. Since heparan sulfate is a modulator of a number of neuronal molecules, we hope to identify functional networks of molecules underlying autism and other childhood mental disorders.
Matsumoto K, Irie F, Mackem S, Yamaguchi Y
Proc Natl Acad Sci U S A 2010 Jun 15 ;107(24):10932-7Matsumoto Y, Matsumoto K, Irie F, Fukushi J, Stallcup WB, Yamaguchi Y
J Biol Chem 2010 Jun 18 ;285(25):19227-34Kraushaar DC, Yamaguchi Y, Wang L
J Biol Chem 2010 Feb 19 ;285(8):5907-16Dr. 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.
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.
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
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.
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
Gommerman JL, Browning JL, Ware CF
Cytokine Growth Factor Rev 2014 Apr ;25(2):139-45Cheung TC, Coppieters K, Sanjo H, Oborne LM, Norris PS, Coddington A, Granger SW, Elewaut D, Ware CF
J Immunol 2010 Aug 1 ;185(3):1949-58Cheung 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):7286-96Dr. 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.”
Postdoctoral Fellowship, Stanford University School of Medicine
PhD in Cellular Molecular Medicine, University of Ottawa, Canada
BS in Biomedical Sciences, University of Ottawa, Canada
2020: NINDS K99/R00 Pathway to Independence Award
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
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.”
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.
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):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.e6Dumont NA, Wang YX, von Maltzahn J, Pasut A, Bentzinger CF, Brun CE, Rudnicki MA
Nat Med 2015 Dec ;21(12):1455-63Eric has a broad background in chemical biology, with specific training and expertise in kinase inhibitors and targeted protein degradation, an emerging modality in which small molecules recruit E3 ligase complexes to target proteins to induce their ubiquitination and subsequent proteasomal degradation. He also has experience in pharmacological modulation of immune cells to improve anti-tumor immunity.
He received his PhD from the University of California San Francisco and postdoctoral training at the Dana-Farber Cancer Institute.
2021: Postdoctoral Fellow, Dana-Farber Cancer Institute / Harvard Medical School
2009: PhD, University of California San Francisco, 2015 BS, Duke University
Damon Runyon Cancer Research Foundation Fellowship
Related Disease
Cancer, Immune Disorders, Molecular Biology
Phenomena or Processes
Adaptive Immunity, Cancer Biology, Cell Biology, Disease Therapies, Tumor Microenvironment
Techniques and Technologies
Chemical Biology, Drug Discovery
Dysregulation of transcriptional circuits is a common hallmark of disease, and in particular is found in both tumor and host immune cells in cancer. Eric’s lab is focusing on developing and using chemical tools to modulate the activity of key transcriptional regulators of both tumor cells and host immune cells, with a long-term goal of identifying new therapeutic approaches.
Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, Ivanova E, Paweletz CP, Bowden M, Zhou CW, Herter-Sprie GS, Sorrentino JA, Bisi JE, Lizotte PH, Merlino AA, Quinn MM, Bufe LE, Yang A, Zhang Y, Zhang H, Gao P, Chen T, Cavanaugh ME, Rode AJ, Haines E, Roberts PJ, Strum JC, Richards WG, Lorch JH, Parangi S, Gunda V, Boland GM, Bueno R, Palakurthi S, Freeman GJ, Ritz J, Haining WN, Sharpless NE, Arthanari H, Shapiro GI, Barbie DA, Gray NS, Wong KK
Cancer Discov 2018 Feb ;8(2):216-233Dobrovolsky D, Wang ES, Morrow S, Leahy C, Faust T, Nowak RP, Donovan KA, Yang G, Li Z, Fischer ES, Treon SP, Weinstock DM, Gray NS
Blood 2019 Feb 28 ;133(9):952-961Wang ES, Verano AL, Nowak RP, Yuan JC, Donovan KA, Eleuteri NA, Yue H, Ngo KH, Lizotte PH, Gokhale PC, Gray NS, Fischer ES
Nat Chem Biol 2021 Jun ;17(6):711-717Kristiina Vuori earned her MD and PhD at University of Oulu, Finland. After completion of internship and residency, she received postdoctoral training at the Institute and was appointed to faculty in 1996. Dr. Vuori was selected as a PEW Scholar in the Biomedical Sciences in 1997. She has been co-Director of the Conrad Prebys Center for Chemical Genomics, housed at Sanford Burnham Prebys, since its inception in 2005. She was appointed Deputy Director of the Institute’s NCI-Designated Cancer Center in 2003, and Director of the Cancer Center in 2006. In 2008, she was appointed Executive Vice President for Scientific Affairs at Sanford Burnham Prebys. She was President of the Institute from 2010 to 2022.
Related Disease
Brain Cancer, Breast Cancer, Cancer, Leukemia/Lymphoma, Lung Cancer, Ovarian Cancer, Prostate Cancer
Dr. Vuori’s research is aimed at unraveling the cell mechanisms of the most life-threatening aspect of cancer, which is cancer metastasis. Metastasis is responsible for nearly all deaths in cancer patients, and understanding of the mechanisms that turn a cancer from a locally growing tumor into highly metastatic cancer cells will provide clues how to prevent this step in cancer progression. All cells in our body stick to one another and to the packaging material, or extracellular matrix, around them. This adhesion is essential for cell survival; if cells become detached from their microenvironment, they will die through a process known as apoptosis. This phenomenon, which is called adhesion dependency of survival, is one of the safeguards that maintain the integrity and normal function of tissues, and prevent cells from becoming cancerous. Normal cells cannot detach from their tissue and establish themselves somewhere else, because they will die on the way. Yet cancer cells somehow get around this requirement; they trespass aggressively into other tissues and metastasize to distant sites in the body without dying. Dr. Vuori’s work is aimed at identifying the molecular mechanisms that in normal cells makes them adhesion-dependent; false action of the very same mechanisms is likely to be the key step in allowing cancer cells to metastasize.
Cipres A, O’Malley DP, Li K, Finlay D, Baran PS, Vuori K
ACS Chem Biol 2010 Feb 19 ;5(2):195-202Finlay D, Howes A, Vuori K
Cancer Res 2009 Jun 15 ;69(12):5023-9Côté JF, Vuori K
Science 2009 Apr 17 ;324(5925):346-7Dr. Xiao Tian participates in the Degenerative Diseases Program and the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys. He started his lab in 2024 to understand the fundamental biology of aging and its contribution to age-related diseases. He joined the Institute after his postdoctoral research in Dr. David Sinclair’s lab at Harvard Medical School where he co-wrote the Information Theory of Aging. He obtained his BS from Shandong University and his PhD from the University of Rochester where he worked with Dr. Vera Gorbunova.
2018-2023: Postdoc, Harvard Medical School
2016-2018: Postdoc, University of Rochester
2010-2016: PhD, Biology of Aging, University of Rochester
2005-2009: BS, Microbial Technology, Shandong University
2020-2026: K99/R00 Pathway to Independence Awards, NIH/NIA
2019-2020: NASA Postdoctoral Fellowship, NASA Ames Research Center
2017: Outstanding Dissertation Award for the Natural Sciences, University of Rochester
2015: Messersmith Dissertation Fellowship, University of Rochester
2014: Award for Outstanding Self-Financed Students Abroad, China Scholarship Council
2010-2014: Holtfreter Fellowship, University of Rochester
2007: Weichai Power Scholarship, Shandong University
2006-2008: Excellent Student Scholarship, Shandong University
Related Disease
Aging-Related Diseases, Alzheimer’s Disease, Cancer
Phenomena or Processes
Aging, Epigenetics, Genomic Instability, Neurodegeneration
Research Models
Computational Modeling, Mouse, Naked Mole Rat, Primary Human Cells
Techniques and Technologies
Bioinformatics, Epigenomics, Gene Expression, Gene Knockout (Complete and Conditional), High-Throughput/Robotic Screening, Mouse Behavioral Analysis
The Tian lab studies the fundamental mechanisms of aging and their roles in the onset of age-related diseases. Our recent research in epigenetic reprogramming and aging clocks indicates that the progressive loss of epigenetic information over time is a key driver of aging. The current research of the lab focuses on understanding how the epigenetic landscape is set up and maintained and investigating why the maintenance system fails which leads to aging and related diseases including cancer and neurodegeneration. Building on this, our ultimate goal is to develop safe and effective rejuvenation strategies to counteract aging.
Below are my major contributions to the field of aging research during my PhD and postdoc work:
Uncovering the first anti-cancer and longevity mechanism of the naked mole rat
We identified high-molecular-mass hyaluronan (HMM HA) as a critical mechanism for the cancer resistance of the naked mole-rat cells. Furthermore, we found that this anti-cancer and longevity mechanism from naked mole rats can be integrated into other species, highlighting the significant implications of identifying new mechanisms from long-lived species. Our goal is to decipher how long-lived organisms control the pace of aging and deter age-related diseases.
Discovering enhanced DNA double-strand break (DSB) repair in long-lived species
Using a group of 18 species, we revealed that long-lived species possess efficient DNA double-strand break repair, mediated by potent SIRT6 activities. Future directions include deciphering how long-lived species address different types of cellular stress to maintain genomic and epigenomic stability.
Epigenetic reprogramming as a strategy to counteract aging and age-related diseases
We illustrated that epigenetic information loss as a result of DNA damage repair is a key driver of aging. One interventional strategy is to recover the lost epigenetic information, such as through reprogramming. We revealed that epigenetic reprogramming is an effective strategy to counteract aging and even potentially modify the trajectory of age-related diseases including glaucoma. We are currently testing other disease settings.
Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, Karg MM, Schultz MB, Kane AE, Davidsohn N, Korobkina E, Chwalek K, Rajman LA, Church GM, Hochedlinger K, Gladyshev VN, Horvath S, Levine ME, Gregory-Ksander MS, Ksander BR, He Z, Sinclair DA
Nature 2020 Dec ;588(7836):124-129Tian X, Firsanov D, Zhang Z, Cheng Y, Luo L, Tombline G, Tan R, Simon M, Henderson S, Steffan J, Goldfarb A, Tam J, Zheng K, Cornwell A, Johnson A, Yang JN, Mao Z, Manta B, Dang W, Zhang Z, Vijg J, Wolfe A, Moody K, Kennedy BK, Bohmann D, Gladyshev VN, Seluanov A, Gorbunova V
Cell 2019 Apr 18 ;177(3):622-638.e22Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, Seluanov A
Nature 2013 Jul 18 ;499(7458):346-9
Phenomena or Processes
Actin Cytoskeleton, Adipocyte Differentiation, Aging, Apoptosis and Cell Death, Cancer Biology, Cancer Metabolism, Cancer-Associated Glycans, Cell Adhesion and Migration, Cell Differentiation, Cell Signaling, Combinatorial Therapies, Damage-Associated Molecular Patterns, Extracellular Matrix, Glycosylation, Inflammation, Innate Immunity, Integrins, Metabolic Networks, Mitochondrial Biology, Organic/Synthetic/Medicinal Chemistry, Tumor Microenvironment, Tumorigenesis
Anatomical Systems and Sites
Adipose Tissue, General Cell Biology, Immune System and Inflammation, Mammary Gland, Vasculature
Research Models
C. elegans, Human, Human Cell Lines, Mouse, Mouse Cell Lines, Primary Cells
