The Role of Secretory Pathway Kinases in Stem Cell Differentiation
There is an urgent need for a cure of diabetes. Islet transplantation has shown promise in curing type 1 diabetes; however, an obstacle toward implementation of this therapy is the shortage of engraftable islets. Human embryonic stem cells (hESCs) can differentiate into all cell types and are potentially an unlimited source of pancreatic β cells. Unfortunately, the lack of defined conditions for reproducibly differentiating hESCs into endocrine precursors (EPs), effective strategies to purify these EPs to avoid teratoma risk, and the destruction of engrafted islets by immune rejection despite immune suppression greatly hinder clinical development of this promising therapy.
Our research is directed at identifying factors necessary to derive β-cells from hESCs. Our recent identification of a novel family of secretory kinases has led us to investigate the roles of these enzymes in hESC differentiation. However, their roles in hESC differentiation remain poorly understood. A myriad of secreted proteins are phosphorylated, including growth factors, cell surface proteins, and extracellular matrix proteins that are critical for stem cell renewal and differentiation. This research will allow us to clarify the role of secreted kinases in hESC differentiation and define a secreted kinase phosphoproteome for pancreatic endocrine cells to aid in identifying specific factors that may facilitate the development of tractable methods to generate islet cells for transplantation.
Diabetes has devastating consequences on those afflicted and on State healthcare costs. Given the staggering rise in both occurrence and cost, diabetes possesses the potential to overwhelm our healthcare system. In 2007, diabetes directly affected 1 in 10 Californians (2.7 million), costing the state $24.5B annually. Current stem cell therapies for type 1 diabetes mellitus (T1DM) suffer from deficiencies that render them ineffective for long-term treatment. As an Exploratory Concepts application, this research would benefit the State of California and its citizens on multiple fronts. First, positive results will provide a foundation to facilitate and expedite the development of improved cell-based therapies for T1DM. Second, fostering the successful creation of progenitor cells for chronic diseases such as diabetes will enhance prospects for increasing the numbers of research personnel in both academia and biotech companies. Finally, this work may obviate the need for immune suppression therapy that carries serious side effects including propensity to infections, hypertension, and damage to the transplanted cells, which can occur following islet transplantation procedures. The research outlined in this proposal will provide a better understanding of the stem cell biology in order to create tractable stem cell therapies for treatment of T1DM that minimize these complications and reduce health care expenses directly attributed to diabetes and its complications.