The Whittier Diabetes Research Program

The Whittier Diabetes Research Program is a collaborative effort to fight diabetes – on the forefront of pursuing a “cure” while also developing strides in minimizing diabetes complications. This battle includes seventeen principal investigators (PIs) and dozens of researchers focusing their efforts on cutting-edge research, including the areas of:

• The molecular pathways of insulin action and resistance
• The secrets of glucose metabolism
• The causes of peripheral neuropathy, a painful complication affecting the extremities
• The complication of atherosclerosis, in which diabetes is a leading cause
• The development of cell-based therapy for type 1, of which one of the most important advances was replication of insulin-producing cells outside the body- a crucial step in the path to a possible “cure”

Research Activities. The Islet/Stem Cell Research Laboratory at the Whittier Institute. The development of the pancreas: implications for therapies in type 1 diabetes. Pancreatic development occurs as a continuum, beginning at embryonic stem cells. Understanding the molecular events that drive the genesis of functional insulin-producing cells from undifferentiated stem cells is critical to devise strategies that will help restore and/or maintain beta cell mass. The four projects described in this application are unified to delineate specific processes that occur during islet development.

• Project 1. Differentiation of pancreatic endocrine cells. Dr. A. Hayek, the principal investigator for the grant, is an experienced researcher in type 1 diabetes. Trained at Yale and Harvard, he is a recognized authority in the biology of pancreatic islets as it applies to potential cell-based therapies in diabetes. In this project, Dr. Hayek proposes to induce human embryonic stem cells (hESCs) and pancreatic progenitor cells into insulin-producing cells by recapitulating embryonic pancreas development. Building upon an established protocol to induce definitive endoderm, the initial step in pancreas formation, Dr. Hayek will generate methods to achieve the transition from definitive endoderm to pancreatic progenitors using a combination of gene transfer experiments, inducible factors (in conjunction with Dr. I. Afrikanova), and specific proteins such as the chemokine/chemokine receptor pair SDF-1-CXCR4 (With Dr. Ayse Kayali). Joining Project 1 is Dr. A. Pasquinelli, an assistant professor in the Department of Biology at UCSD doing innovative research on the role of micro RNAs (miRNAs), a new class of regulatory RNAs. The objective is to determine how specific miRNAs and their target genes contribute to differentiation events that precede pancreas development.

• Project 2. An integrated signaling and proteomics-based approach to study progenitor cell differentiation. Dr. C.C. King, the principal investigator for project 2 is currently an Assistant Research Scientist in the Department of Pediatrics at UCSD. Dr. King is an expert in proteomics, a new field that strives to identify and characterize all expressed proteins within a specific cell. His work is focused on mapping thehuman islet proteome and identifying changes in protein expression patterns that occur during islet development and expansion. In this project, Dr. King will build upon his existing proteomic maps to determine how changes in signal transduction are correlated with changes in protein expression during islet development. The objective is to demonstrate whether temporal activation of signaling pathways can be mapped to globalchanges in protein expression. Specifically, he will 1) analyze temporal activity of three signaling pathways as hESC cells are differentiated to definitive endoderm and towards a pancreatic lineage and 2) link the signaling changes to global changes in protein expression.

• Project 3. Molecular regulation of β-cell epithelial to mesenchymal transition. Dr. U. Jhala, the principal investigator for project 3 is currently an Assistant Research Scientist in the Department of Pediatrics at UCSD. Dr. Jhala has had extensive training in both transcriptional regulation and signaling mechanisms in β-cell biology. Her current research is focused on understanding the molecular basis of homeostatic mechanisms in maintenance of adult beta cell mass, specifically studying the role of signaling cascades in β-cell death and themolecular events that regulate the growth of beta cells. In this project, we will examine the role of an adaptor protein that mediates the transition of a β-cell from growth to differentiation. The objective is to better understand the role of the protein CtBP as a master regulator of the transition phase from growing to differentiated cells and vice versa. This project is designed to identify the targets of CtBP and examine how these targets execute such a complex transition in molecular terms.

• Project 4. Role of neural chemotrophic factors in islet cell development. Dr. V. Cirulli, the principal investigator for project 4 is an Associate Research Scientist in the Department of Pediatrics at UCSD, and an established investigator in pancreas development. His studies focus on Netrins, a family of chemotropic neural factors. Building on his most recent work demonstrating the expression of Netrins in the developing human pancreas, he hypothesizes that the coordinated interaction of cells with Netrins may play important adhesive/migratory functions, as well as exert instructive roles for growth and/or differentiation, all processes essential to the emergence and development of specific pancreatic cell lineages. The objective is to determineto what extent Netrins contribute distinct developmental cues for developing pancreatic cell populations.

• Past accomplishment from our lab include: We demonstrated that a) insulin producing cells are expandable, and can retain function during this process when maintained as 3D structures; b) we determined that specific integrins are crucial for islet function prior to, during, and after ex vivo expansion, and c) that special neural factors (Netrins) are important regulators of islet cell adhesion and migration during development

The internationally recognized roster of PIs and their respective work has placed the Research Program among the world’s leading diabetes research efforts.