Type 1 Diabetes Archives - Sanford Burnham Prebys

Alexander Strongin earned his PhD from Moscow State University in Russia in 1972 and his D.Sci. degree from the Institute of Microbial Genetics in Moscow in 1983. From 1982 to 1988, Dr. Strongin was head of the Laboratory of Functional Enzymology at the Institute of Genetics of Microorganisms in Moscow. He served as head of the Department of Biotechnology and Laboratory of Protein Engineering, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, from 1988 to 1990. From 1990 to 1994, he was a visiting professor of biochemistry in the Division of Dermatology at Washington University School of Medicine, St. Louis, Missouri. Dr. Strongin has worked in the La Jolla area since 1994, as senior staff scientist in the Biology Division at General Atomics, 1994-1995, and as senior staff scientist at the La Jolla Institute for Experimental Medicine, 1995-1999. Dr. Strongin joined Sanford Burnham Prebys on September 1, 1999.

Related Disease
Anthrax, Arthritis, Brain Cancer, Breast Cancer, Cancer, Hepatitis C, Multiple Sclerosis, Prostate Cancer, Type 1 Diabetes

Tumors produce unique enzymes, which by degrading the normal tissue provide an opportunity for tumor to grow in size and metastasize. These enzymes are called matrix metalloproteinases or MMPs. MMPs are a primary target for the design of anti-cancer pharmaceuticals. Our work aims to lay the foundation from which efficient therapeutics could ultimately be derived. Dr Strongin’s research is focused on the fundamental mechanisms involving MMPs in the processes of cell migration, cell proliferation and metastasis. The far-reaching goals of this pioneering research are to gain an understanding of how MMPs by cleaving the surrounding tissue and by affecting cell surface receptors govern locomotion of malignant cells. This knowledge is critical for design of efficient pharmaceuticals that may find applications in a variety of disease conditions including cancer, arthritis and stroke.

Alex Strongin’s Research Report

Degradation of the extracellular matrix and tissue remodeling play critical roles in tumor progression, particularly in invasion, metastasis, and neovascularization. Matrix metalloproteinases (MMPs) are essential for matrix proteolysis. Understanding the roles of MMPs in tumor growth and angiogenesis is of paramount importance to novel strategies for treatment of malignant tumors. Our primary goal is to characterize mechanisms of MMP activation involved in spatial and temporal control of focal proteolysis and to increase knowledge of cell-mediated matrix remodeling. Recently, we showed that heteromolecular assemblies involving MMPs and integrins that can simultaneously activate and dock MMPs are present on the surfaces of tumor cells. Apparently, these mechanisms of MMP activation are instrumental in clustering activated proteinases and integrins at the protrusions at the invasive front of migrating cells and at the invasive front of tumors (see Figure).

Interactions between MMPs and integrins, critical to spatial and temporal control of proteolysis, most likely are common for many cell types. To test our hypotheses and to outline novel approaches to control the activity of MMPs, we are examining mechanisms involved in activation, docking, and cross talk of MMPs and integrins in vivo and in vitro. We expect to experimentally show at the cell and protein sequence levels how the temporal and spatial regulation of matrix degradation is linked to dynamic changes of cell shape and cytoskeleton and to identify molecular mechanisms of cell motility. The immediate results of these studies will be improved diagnosis and treatment of malignant neoplasms.

Schematic depiction of the MMP-integrin molecular assembly. Inhibitory effects of tissue inhibitors of metalloproteinases (TIMPs) and the C-terminal domain of MMP-2 are shown by black arrows. The conversions of MMP-2 are shown by open arrows. The question mark stands for a cytoskeletal protein involved in a complex with membrane type-1 matrix metalloproteinase (MT1-MMP). This assembly is critical for docking, activation, and cross talk of MMPs and integrins and is intimately involved in regulating focalized matrix degradation and cell locomotion. MT1-MMP is in immediate proximity to integrin alpha vbeta 3. Both MT1-MMP and the integrin associate with the cytoskeleton. TIMP-2 links MT1-MMP (“a receptor”) and the secretory MMP-2 proenzyme. The second molecule of MT1-MMP (“an activator” that is free of TIMP-2) activates integrin alpha vbeta 3 by limited proteolysis of the beta 3 integrin subunit. The activator initiates the activation of pro-MMP-2 by cleaving the N-terminal part of the 68-kDa MMP-2 latent zymogen. The 64-kDa activation intermediate of MMP-2 efficiently associates with activated integrin alpha vbeta 3 via the C-terminal domain of the enzyme. The 64-kDa to 62-kDa autocatalytic maturation occurs if MMP-2 is complexed with the integrin. The mature MMP-2 enzyme transiently associated with the integrin at the surface of tumor cells accelerates the directional invasion of the cells. Additionally, if transiently complexed with the integrin at the surface of host stromal cells, the enzyme facilitates tumor neovascularization. TIMPs, including TIMP-2 and TIMP-1, efficiently inhibit the activity of soluble MMP-2. By providing links between integrins, MMPs, and TIMPs and, more generally, between cell shape and focal proteolysis, this model represents basic mechanisms of pro-MMP-2 activation and illustrates a coordinated interplay of inhibitors, proteinases, and integrin adhesion receptors at cell surfaces.

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Showing 2 of 2

Structural and functional parameters of the flaviviral protease: a promising antiviral drug target.

Shiryaev SA, Strongin AY

Future Virol 2010 Sep 1 ;5(5):593-606

Virtual ligand screening of the National Cancer Institute (NCI) compound library leads to the allosteric inhibitory scaffolds of the West Nile Virus NS3 proteinase.

Shiryaev SA, Cheltsov AV, Gawlik K, Ratnikov BI, Strongin AY

Assay Drug Dev Technol 2011 Feb ;9(1):69-78

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Dr. Levine is Emeritus Professor at Sanford Burnham Prebys. Prior to that, he was a Professor in the Department of Pediatrics at the University of California, San Diego School of Medicine, where he continues to see children with inherited metabolic diseases. Dr. Levine received his undergraduate degree in biochemistry from Harvard and his MD and PhD degree in genetics from the University of Washington. His clinical training as a pediatric geneticist was at the Children’s Hospital of Philadelphia. Dr. Levine has been working in the field of cell transplantation therapies for diabetes and b-cell biology for more than fifteen years. His laboratory was the first to develop immortalized cell lines from the human endocrine pancreas as models of beta-cell growth and differentiation. He has made insights into cellular senescence in the endocrine pancreas, finding that b-cells undergo rapid senescence when stimulated to proliferate. Most recently, he and his co-workers demonstrated the existence of endocrine stem cells in the adult human pancreas. The laboratory continues to pursue the development of cell therapies for diabetes using a variety of approaches, including high throughput screening.

Education

1979-86: PhD, University of Washington (Genetics)
1979-86: MD, University of Washington
1975-79: A.B., Harvard University (Biochemistry)

Postgraduate Training

1989-91: Genetics Fellow, Dept. of Pediatrics, UCSD School of Medicine
1988-89: Clinical Genetics Fellow, Children’s Hosp. of Philadelphia
1987-89: Pediatric Resident, Children’s Hosp. of Philadelphia
1986-87: Pediatric Intern, Children’s Hosp. of Philadelphia

Other Appointments

Health Sciences Clinical Professor of Pediatrics, UCSD School of Medicine
Attending Physician, Rady Children’s Hospital

Related Disease
Cancer, Childhood Diseases, Metabolic Diseases, Obesity, Type 1 Diabetes, Type 2 Diabetes

Diabetes is a disease in which there is an insufficient amount of insulin, produced by the pancreatic b-cells, to control the blood glucose concentration. In type I diabetes, the b-cell are destroyed by an autoimmune response, while in type II diabetes, the b-cells are dysfunctional and are ultimately lost because of obesity-associated pathology. Our laboratory is interested in how b-cells regenerate under normal and pathophysiological conditions, with the goal of developing new therapies for diabetes that result in an increased number of those cells. Our studies of b-cell growth have also led us to develop lead compounds that are active in cancer, an interesting connection as both obesity and diabetes are now recognized as major risk factors for cancer.

Fred Levine’s Research Report

The major interest in the laboratory is pancreatic beta-cell biology and specifically the control of beta-cell growth and differentiation in the adult pancreas. In both type I and type II diabetes, β-cell mass decreases and is a major factor in the pathogenesis of diabetes. Thus, one major question in which we are interested is the existence and nature of adult endocrine stem/progenitor cells. Using both human and rodent models, we study cells in vitro and in vivo to determine the competence of various cell populations to undergo endocrine differentiation in response to defined stimuli. The goal is to achieve a sufficient understanding of the process of adult β-cell regeneration to allow us to enhance β-cell mass in diabetes.

A second major area of emphasis is to use high-throughput screening to discover compounds that modulate important aspects of β-cell biology. Our focus has been on modulation of insulin promoter activity, as that gene is acted upon by many diabetogenic stimuli. We have isolated and are characterizing a number of compounds and genes that were discovered in the screening process. Recently, we have discovered ligands for the orphan nuclear receptor HNF4a. HNF4a is involved in a number of disease processes, including diabetes, liver disease, and cancer.

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Showing 3 of 3

HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.

Kiselyuk A, Lee SH, Farber-Katz S, Zhang M, Athavankar S, Cohen T, Pinkerton AB, Ye M, Bushway P, Richardson AD, Hostetler HA, Rodriguez-Lee M, Huang L, Spangler B, Smith L, Higginbotham J, Cashman J, Freeze H, Itkin-Ansari P, Dawson MI, Schroeder F, Cang Y, Mercola M, Levine F

Chem Biol 2012 Jul 27 ;19(7):806-18

Induction of β-cell replication by a synthetic HNF4α antagonist.

Lee SH, Piran R, Keinan E, Pinkerton A, Levine F

Stem Cells 2013 Nov ;31(11):2396-407

Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells.

Lee SH, Hao E, Levine F, Itkin-Ansari P

Islets 2011 Nov-Dec ;3(6):358-66

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A career history of fundamental discovery and translational research in immunology has guided Dr. Ware to identify new drug targets and develop novel therapeutics. Dr. Ware’s career in immunology and virology began in 1982 when he became a Professor at the University of California, Riverside’s Division of Biomedical Sciences. In 1996, he joined the La Jolla Institute for Immunology in San Diego as Head of the Division of Molecular Immunology. Professor Ware joined Sanford Burnham Prebys Medical Discovery Institute in 2010, serving as the Director of the Infectious and Inflammatory Disease Center and Adjunct Professor of Biology at the University of California at San Diego. He is currently the Director of the Laboratory of Molecular Immunology, which focuses on discovering and designing immunotherapeutics.

As an educator, he taught medical students immunology and virology. He trained over 60 postdoctoral fellows and graduate students who chose careers in research in academic and pharmaceutical science, patent law, or teaching.

Dr. Ware advises scientific panels and review boards for the National Institutes of Health and serves on the scientific advisor boards for the Allen Institute for Immunology and the Arthritis National Research Foundation. Scientific advisor with several biotechnology and pharmaceutical companies on immunotherapy for cancer and autoimmune diseases using innovative approaches to target discovery and drug development.

Dr. Ware’s research program is dedicated to unraveling the intricate intercellular communication pathways that govern immune responses. His work, which centers on cytokines in the Tumor Necrosis Factor (TNF) Superfamily, particularly those that regulate cell survival and death in response to viral pathogens, spans the domains of cancer,autoimmune and infectious diseases.

At Sanford Burnham Prebys, Dr. Ware is pivotal in promoting the translation of the faculty’s scientific discoveries. His efforts have led to the Institute’s reputation as a productive and preferred partner in collaborations with Pharma, including multi-year research and drug development projects with Eli Lilly and Avalo Therapeutics. His success translating fundamental knowledge into rational drug design has led to three novel therapeutics targeting inflammatory pathways, currently in clinical trials.

Education

1981-1982: T cell Immunology, Dana-Farber Cancer Institute of Harvard Medical School in Boston, MA. Tim Springer and Jack Strominger, advisors.
1979-1981: Biochemistry of Complement, University of Texas Health Science Center, San Antonio, TX. W Kolb, advisor
1974-1979: PhD in Molecular Biology and Biochemistry from the University of California, Irvine; Gale Granger, PhD mentor.

Honors and Recognition

Distinguished Fellow, American Association of Immunologists
Honorary Lifetime Membership Award International Cytokine and Interferon Society
Hans J. Muller-Eberhardt Memorial Lecture
Biotech All Star, San Diego Padres Award
“Pillars of Immunology” discovery of the Lymphotoxin-b Receptor, published in Science
Outstanding Alumnus, Ayala School of Biological Sciences, University of California, Irvine
National MERIT Award R37 (10 years), National Institute of Allergy and Infectious Disease, NIH
National Research Service Award, NIH Postdoctoral Fellowship

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

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

Discovery of the TNF-LIGHT-LTαβ Network

The molecular elements of this cellular communication network were revealed with our discovery of Lymphotoxin-β and its formation of the trimeric heterocomplex with LTαβ¹ and its signaling receptor, Lymphotoxin-β Receptor². The LTβR revealed a new inter-cellular communication pathway that provides a key mechanism underlying the development and homeostasis of lymphoid organs. A second ligand we discovered, LIGHT (TNFSF14), is a novel ligand for the herpesvirus entry mediator (HVEM; TNFRSF14), and surprisingly, the LTβR³ heralding the concept that TNF, LTαβ, and LIGHT form an integrated signaling network thru distinct receptors controlling inflammation and host defense.⁴

LTβR Signaling in Host Defense and Immune Evasion

Our investigations into the mechanisms of virus evasion of the immune system revealed an essential role of the LTβR pathway in regulating the type 1 interferon response to cytomegalovirus⁵ and now recognized as a major defense against other pathogens. LTβR signals differentiate macrophages and stromal cells into IFN-producing cells. LTβR transcriptomics and proteomics datasets we generated revealed a novel constellation of anti-viral host defense mechanisms⁶. Importantly the role of the LTβR pathway to alter tissue microenvironments by differentiation of specialized stromal cells has implications for promoting effective immune responses to cancer.

Discovery of the HVEM-BTLA Immune Checkpoint

The LTBR-HVEM-BTLA Network in the TNF Superfamilies. Arrows indicate ligand-receptor binding (black), inhibitors (red arrow) and bidirectional signaling (dual arrowheads); HSV, herpes simplex virus; CMV, human cytomegalovirus. BTLA and CD160 are Ig Superfamily proteins. BTLA is an inhibitory checkpoint receptor; DcR3, decoy receptor 3 inhibits LIGHT binding to HVEM and LTBR.

The discovery that HVEM is a coreceptor for the immune checkpoint, B and T lymphocyte attenuator (BTLA), an Ig superfamily member, established a new paradigm in TNF Receptor signaling pathways ⁷. Additional investigations revealed the importance of the HVEM-BTLA system in limiting immune responses, including T cell help for B cell clonal expansion, antibody maturation, and secretion⁸. HVEM-BTLA also regulates control of the intestinal microbiome, limiting invasion of pathogenic bacteria and enhancing Treg cell homeostasis ⁹. The diverse roles of this pathway are seen in the loss of BTLA signaling from mutations in HVEM frequently present in B cell lymphomas¹⁰. Additional layers of immune regulators, CD160 and DcR3, control the LIGHT-HVEM-BTLA pathways, revealing this network as a key mechanism controlling immune homeostasis.

Appreciating the fundamental features of the TNF-LIGHT-LTab Network in effector and homeostasis mechanisms presents a target-rich resource for therapeutic intervention in autoimmunity, infection, and cancer^{11, 12}.

Translational research and Immunotherapy

2021-current: Lead Scientific Advisor, Avalo Therapeutics
A neutralizing, fully human mAb (quisovalimab) to the proinflammatory cytokine LIGHT (TNFSF14) completed Phase I with an excellent safety profile and a Phase II trial establishing efficacy in COVID-19 pneumonia (NCT0441205)¹³. We identified elevated serum levels of LIGHT in hospitalized patients with COVID19¹⁴ spurring a randomized, double-blind, multicenter, proof-of-concept trial with adults hospitalized with COVID-19-associated pneumonia and mild to moderate ARDS¹⁵. The results established efficacy with a significant proportion of patients remaining alive and free of respiratory failure through day 28 after receiving quisovalimab, most pronounced in patients >60 years of age (76.5% vs. 47.1%, respectively; P = 0.042). These results and animal models validated LIGHT as a target for non-COVID inflammatory conditions, clinical trials ongoing in asthma (NCT05288504)¹².
2021-current: Principal Investigator, Avalo Therapeutics – Sanford Burnham Prebys collaboration
Bioengineered a first-in-class checkpoint agonist targeting BTLA immune checkpoint¹⁶ in preclinical development
2019-current: Director and Principal Investigator, Fair Journey Biologics – Sanford Burnham Prebys collaboration
Immunotherapy for TNBC and PANC, in preclinical development
2015-2022: Director and Lead Principal Investigator, LILLY-Sanford Burnham Prebys Collaboration in Autoimmunity
Collaborative research partnership with Eli Lilly involved target discovery and therapeutic development directed at immune regulators for autoimmune diseases. The collaboration produced three novel biologics currently in Phase I/2 trials (NCT03933943). The collaboration included a target discovery platform for T cell effector memory and NK cell immunomodulators.
2015-2020: Lead Principal Investigator, Sanford Burnham Prebys – Capella Biosciences collaboration
Created a fully human mAb specific for membrane LIGHT (CBS001); phase I initiated (NCT05323110).
2016-2020: Lead Scientific Investigator, Boehringer Ingelheim – Sanford Burnham Prebys Collaboration
Target discovery collaboration in inflammatory and fibrotic diseases⁶
2012-2014: Pfizer Innovation Center, Principal Investigator Bioengineering TNFR Superfamily in Autoimmune disease

1. Browning, J.L. et al. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72,847-856 (1993).
2. Crowe, P.D. et al. A lymphotoxin-beta-specific receptor. Science 264,707-710 (1994).
3. Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8,21-30 (1998).
4. Ward-Kavanagh, L.K., Lin, W.W., Sedy, J.R. & Ware, C.F. The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses. Immunity 44,1005-1019 (2016).
5. Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3,67-76 (2008).
6. Virgen-Slane, R. et al. Cutting Edge: The RNA-Binding Protein Ewing Sarcoma Is a Novel Modulator of Lymphotoxin beta Receptor Signaling. J Immunol 204,1085-1090 (2020).
7. Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6,90-98 (2005).
8. Mintz, M.A. et al. The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis. Immunity 51,310-323 e317 (2019).
9. Stienne, C. et al. Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa. Cell reports 38,110553 (2022).
10. Sedy, J.R. & Ramezani-Rad, P. HVEM network signaling in cancer. Adv Cancer Res 142,145-186 (2019).
11. Croft, M., Benedict, C.A. & Ware, C.F. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12,147-168 (2013).
12. Ware, C.F., Croft, M. & Neil, G.A. Realigning the LIGHT signaling network to control dysregulated inflammation. J Exp Med 219 (2022).
13. Zhang, M., Perrin, L. & Pardo, P. A Randomized Phase 1 Study to Assess the Safety and Pharmacokinetics of the Subcutaneously Injected Anti-LIGHT Antibody, SAR252067. Clin Pharmacol Drug Dev 6,292-301 (2017).
14. Perlin, D.S. et al. Levels of the TNF-Related Cytokine LIGHT Increase in Hospitalized COVID-19 Patients with Cytokine Release Syndrome and ARDS. mSphere 5 (2020).
15. Perlin, D.S. et al. Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome. J Clin Invest 132 (2022).
16. Sedy, J.R. et al. A herpesvirus entry mediator mutein with selective agonist action for the inhibitory receptor B and T lymphocyte attenuator. J Biol Chem 292,21060-21070 (2017).

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Showing 4 of 4

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Croft M, Salek-Ardakani S, Ware CF

Nat Rev Drug Discov 2024 Dec ;23(12):939-961

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Cheung TC, Atwell S, Bafetti L, Cuenca PD, Froning K, Hendle J, Hickey M, Ho C, Huang J, Lieu R, Lim S, Lippner D, Obungu V, Ward-Kavanagh L, Weichert K, Ware CF, Vendel AC

Structure 2023 Aug 3 ;31(8):958-967.e3

Realigning the LIGHT signaling network to control dysregulated inflammation.

Ware CF, Croft M, Neil GA

J Exp Med 2022 Jul 4 ;219(7):

Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome.

Perlin DS, Neil GA, Anderson C, Zafir-Lavie I, Raines S, Ware CF, Wilkins HJ

J Clin Invest 2022 Feb 1 ;132(3):

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Pamela Itkin-Ansari earned her PhD in Biomedical Sciences from the University of California San Diego, in 1999. She received postdoctoral training focused on juvenile diabetes at that same organization. In 2003, Dr. Itkin-Ansari was appointed Assistant Professor in the Department of Pediatrics and maintains UCSD as her primary affiliation. Dr. Itkin-Ansari was appointed to Sanford Burnham Prebys as an Adjunct Assistant Professor in 2005 and her laboratory is at the Institute.

Other Appointments

UC San Diego
Sanford School of Medicine, South Dakota

Funding Awards and Collaborative Grants

Juvenile Diabetes Research Foundation (JDRF)
California Institute for Regenerative Medicine (CIRM)
The Hartwell Foundation
The Hirshberg Foundation

Honors and Recognition

2012: Invited Speaker, (International) Islet Society, Stockholm, Sweden
2012-current: Editorial Board -Islets
2012-current: Diabetes, Islets, PlosOne, Molecular Therapy- manuscript review
2012-current: Wellcome Trust-grant review
2012: Invited Speaker, Hirshberg Symposium – Pancreatic Cancer
2011: Invited Speaker, American Society of Gene and Cell Therapy, Seattle, Washington
2011: Editorial Board – World Journal of Diabetes
2011: Invited Speaker, UCLA
2011-current: Diabetelogia – manuscript review
2011-current: Editorial Board – World Journal of Diabetes
2010: Invited Speaker, 3rd International Conference on Advanced Technologies & Treatments for Diabetes, Switzerland
2010: Editorial Board -Stem Cell Reviews and Reports [SCRR]
2010: Invited Speaker, American Society of Gene and Cell Therapy, Washington, D.C
2010-current: Hartwell Foundation Biomedical Research Awardee
2010: Invited Speaker, Pancreatic Cancer Research Group, UCLA
2010-current: Faculty Advisor, SDSU CIRM Bridges Program
2009: Invited Speaker, Vanderbilt University, Nashville, Tennessee
2009: Invited Speaker, UK Consulate Stem Cell Meeting
2009: Finalist-NIH President’s New Innovator Award
2009-current: Advances in Experimental Biology and Medicine – manuscript review
2008: Health Hero Award, JDRF and Combined Health Agencies of San Diego
2008-current: Pancreas – manuscript reviewer
2008-current: JDRF – grant reviewer
2007-current: Stem Cells – manuscript reviewer

Other Affiliations

2012-current: Islet Society
2010-current: ASGCT
2008-current: Board of Directors, JDRF San Diego chapter
2008-2013: JDRF board of directors, San Diego
2007-current: American Association for Cancer Research
2007-current: American Diabetes Association
2007-current: American Pediatric Society/Society for Pediatric Research
2006-current: AAAS

Related Disease
Cancer, Diabetes – General, Gastric Cancer, Monogenic Diabetes, Pancreatic Cancer, Type 1 Diabetes, Type 2 Diabetes

Dr. Itkin-Ansari’s research is directed toward understanding diseases of the human pancreas. She has studied the signaling pathways controlling growth and differentiation in the pancreas in order to elucidate mechanisms leading to pancreatic pathogenesis. The lab is developing a cell based therapy for diabetes that will not require immunosuppression. New research in the lab has identified a signaling pathway controlling pancreatic cancer cell growth that is yielding new potential targets for drug discovery for pancreatic cancer.

Pamela Itkin-Ansari’s Research Report

Diabetes

*Genetic engineering in human pancreatic cells*

In Type I, juvenile diabetes, the insulin producing beta-cells in pancreatic islets are destroyed by the immune system and patients require exogenous insulin. In Type II diabetes beta-cells are also lost or dysfunctional and therefore, 25 percent of patients with Type II diabetes also take insulin. Unfortunately, current insulin therapy is not sufficient to prevent serious medical consequences of this disease. Islet transplantation into the liver has been evaluated as a diabetes therapy in adults. However, it is considered too risky for children because transplant patients must take potent drugs to suppress the immune system for the rest of their lives.

The goal of our lab is to develop a human islet transplantation therapy for children that does not require immunosuppression and is minimally invasive. Previously we determined that a durable encapsulation device protected mouse islets from immune rejection in a mouse model of Type I diabetes. The encapsulated cells were controlled diabetes in the animals. In a preclinical trial we demonstrated that the device is also immunoprotective in primates. Recently we have collaborated with a local biotech company ViaCyte in a CIRM funded study to encapsulate human embryonic stem cell derived pancreas cells. Together we demonstrated that the cells differentiate into fully functional islets inside the device and cure diabetes in mice. Remarkably, the cells functioned well even when the device was transplanted just under the skin, making the procedure minimally invasive.

*Islet clusters in the developing pancreas*

We also study the signaling pathways involved in:

beta-cell differentiation
beta-cell function
beta-cell replication and regeneration

Pancreatic Cancer

We are interested in identifying the master regulators of growth control in pancreatic ductal adenocarcinoma (PDA). We found that the transcriptional repressor Id3 is profoundly upregulated in human PDA. To investigate whether Id3 might play an early role in aberrant pancreatic duct cell growth, we expressed the gene in primary human duct cells that are not normally growing. Indeed, Id3 expression was sufficient to trigger cell cycle entry. Further, the lab demonstrated that Id3 is required for pancreatic cancer cell growth. We are now studying Id3 interacting genes in order to identify optimal targets for drug discovery efforts for PDA.

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Showing 3 of 3

HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.

Chem Biol 2012 Jul 27 ;19(7):806-18

Phenothiazine neuroleptics signal to the human insulin promoter as revealed by a novel high-throughput screen.

Kiselyuk A, Farber-Katz S, Cohen T, Lee SH, Geron I, Azimi B, Heynen-Genel S, Singer O, Price J, Mercola M, Itkin-Ansari P, Levine F

J Biomol Screen 2010 Jul ;15(6):663-70

Sources of beta-cells for human cell-based therapies for diabetes.

Itkin-Ansari P, Levine F

Cell Biochem Biophys 2004 ;40(3 Suppl):103-12

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Dr. Dong received his Biology Bachelor of Science degree in 1996 from the University of California, Irvine, where he was involved in molecular evolution and limb regeneration research. He earned his PhD in Cell and Molecular Biology at the University of Wisconsin, Madison in 2002, investigating cell/tissue identity master regulatory genes. His postdoctoral research at the University of California, San Francisco was focused on developmental genetics of the liver and pancreas. Dr. Dong was recruited as an Assistant Professor to Sanford Burnham Prebys Medical Discovery Institute in 2008. He is a recipient of the NIH Director’s New Innovator Award Award and the W. M. Keck Foundation Award, which funds the development of in vivo lineage reprogramming technologies to generate replacement cells and organs directly within a living vertebrate.

Education

BS, Biology, University of California, Irvine
PhD, Cell & Molecular Biology, University of Wisconsin, Madison
Postdoctoral Fellow, Genetics and Development, University of California, San Francisco

Related Disease
Alagille Syndrome, Congenital Diseases, Degenerative Diseases, Liver Diseases, Monogenic Diabetes, Pancreas Diseases, Type 1 Diabetes, Type 2 Diabetes

Phenomena or Processes
Aging, Human Evolution, Organogenesis, Regenerative Medicine

Anatomical Systems and Sites
Developmental Biology, Synthetic Cell Biology

Techniques and Technologies
Developmental Genetics, Disease Genetics

Our objective is to uncover fundamental insight into basic and biomedical science through rigorous investigation of the genetic mechanisms governing organogenesis and diseases. We have discovered multiple genes critical for generating liver and pancreas cells and have created novel animal models for diseases such as diabetes and Alagille Syndrome. These unique experimental models have been yielded mechanistic insight and potential new therapeutic avenues. Further, we have demonstrated for the first time that a cell’s identity can be reprogrammed to convert into a completely unrelated lineage, without their removal from the body (in vivo) and without passage through a stem cell intermediate. This in vivo lineage reprogramming breakthrough may lead to a vast new and safer source of replacement cells for degenerative diseases and injuries. Ultimately, we aim to develop genetic technologies to improve human health and advance human biology.

Kashton (diagnosed with Alagille Syndrome), his mother Shauna, and Professor Dong observing zebrafish
with a mutation in jagged, the gene affected in his disease.

Support Alagille Syndrome Research in Our Lab

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Showing 3 of 3

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Biography

Research

Select Publications

Structural and functional parameters of the flaviviral protease: a promising antiviral drug target.

Virtual ligand screening of the National Cancer Institute (NCI) compound library leads to the allosteric inhibitory scaffolds of the West Nile Virus NS3 proteinase.

Biography

Education

Postgraduate Training

Other Appointments

Research

Select Publications

HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.

Induction of β-cell replication by a synthetic HNF4α antagonist.

Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells.

Biography

Education

Honors and Recognition

Research

Select Publications

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

Epitope topography of agonist antibodies to the checkpoint inhibitory receptor BTLA.

Realigning the LIGHT signaling network to control dysregulated inflammation.

Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome.

Biography

Other Appointments

Funding Awards and Collaborative Grants

Honors and Recognition

Other Affiliations

Research

Select Publications

HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.

Phenothiazine neuroleptics signal to the human insulin promoter as revealed by a novel high-throughput screen.

Sources of beta-cells for human cell-based therapies for diabetes.

Biography

Education

Research

Select Publications

Endoderm Jagged induces liver and pancreas duct lineage in zebrafish.

Identification of Annexin A4 as a hepatopancreas factor involved in liver cell survival.

Specification of hepatopancreas progenitors in zebrafish by hnf1ba and wnt2bb.