? Insulin dependent diabetes mellitus results from the autoimmune destruction of the pancreatic beta cells. Once these crucial cells are lost they cannot be regained since the adult pancreas lacks the ability for regrowth. Therefore, IDDM patients are dependent on the possibility of receiving new endocrine cells to cure their disease. One therapy for IDDM patients is the possibility of utilizing islet stem cells for the in vivo or in vitro growth of new pancreatic islets. Indeed these cells could represent a limitless supply of differentiated beta cells for IDDM patients. However the exact identity of islet stem cells remains unknown despite dramatic progress in the area of islet ontogeny in recent years. Our laboratory has been studying pancreatic islet regeneration in a model where this process occurs vigorously throughout adult life. We have defined a novel cell surface antigen that is expressed on a cell population in the regenerating pancreas as well as in the normal adult gut. In this application we show that cells expressing the PP1 antigen include pancreatic islet stem cells. This work suggests that stem cells that can give rise to functional islets can exist in the normal adult gut. The overall goal of this application is to define the ontogeny and cell surface phenotype of the PP1 expressing pancreatic islet stem cells. We hypothesize that the PP1 antigen marks a population within the normal adult gut and in the regenerating pancreas that includes a high proportion of pancreatic islet stem cells. In this application we will test several mechanistic hypotheses regarding the ontogeny of the PP1 expressing population in the regenerating pancreas. These experiments will elucidate the origin of these cells, and determine how this population arises in the regenerating pancreas. We also propose to establish conditions for expansion of the PP1 expressing population in vitro and define the frequency of islet progenitor cells in this population. Previous comparative microarray data has lead to the identification of several additional candidate cell surface markers that could allow us to further define the identity of pancreatic islet stem cells. These markers will be developed and used for the precise determination of the phenotype of this fascinating cell population in this project. We believe that the experiments contained in this application will define conditions for the identification, characterization and expansion of pancreatic islet stem cells, moving closer towards the goal of a cure for IDDM in humans. ? ?
