This proposal details the research and training plan for Scott Soleimanpour, M.D. to develop his academic career as a physician-scientist focused on the thorough understanding of factors which regulate pancreatic ?-cell replication and survival, with the eventual goal of improving treatment of type 1 diabetes. The career development portion of the proposed K08 award includes an advanced didactic curriculum and formal research mentoring under the supervision of the primary mentor, Doris A. Stoffers, M.D., Ph.D., Associate Professor of Medicine at the University of Pennsylvania School of Medicine, and a multi-disciplinary mentorship committee. The University of Pennsylvania School of Medicine offers a research-rich environment with open access to a wide assortment of expert faculty and resources that will be beneficial in the scientific and professional development of Dr. Soleimanpour. The research proposed in this K08 application will focus on the ?-cell specific role of Clec16a (C-lectin domain family 16, member A), a type 1 diabetes susceptibility gene and novel target of the essential ?-cell transcription factor Pdx1. The Drosophila orthologue of Clec16a, Ema, is an endosomal protein vital to endosomal maturation through direct interaction with the Vps-C HOPS complex, which regulates key transitions in endosome and autophagosome maturation. Loss of Ema function leads to increased growth factor signaling due to decreased clearance of ligand bound receptors with resultant synaptic terminal overgrowth. While Clec16a has been suggested to have restricted expression to immune cells, our preliminary evidence indicates that Clec16a is highly expressed in mouse and human islets. Further, loss of function experiments suggest that Clec16a regulates late endosome accumulation, cell replication, insulin secretion, and mitochondrial respiration in ?-cell lines. Therefore, we hypothesize that Clec16a regulates the ? -cell endosomal pathway and the maintenance of ?-cell mass and function in vivo.
Specific Aim I. To test the hypothesis that Clec16a is critical to ?-cell mass and maintenance of glucose homeostasis.
This aim will determine the role of Clec16a via ?-cell specific loss-of-function experiments in vivo using a conditional Clec16a loxP allele. Experiments will focus on determinations of glucose tolerance and insulin secretion, as well as morphologic analysis of ?-cell mass related to changes in ? -cell proliferation and/or survival.
Specific Aim II. To test the hypothesis that the Pdx1 target Clec16a regulates essential aspects of endosome, autophagosome, and mitochondrial function. Experiments will determine the role of Clec16a in endosomal and autophagosome maturation, endosomal trafficking, and mitochondrial biogenesis and calcium flux. In addition, the upstream regulatory role of Pdx1 in regulation of Clec16a and the ? -cell endosomal pathway will be determined. Through these specific aims, we will establish the role and functional mechanism for a novel Pdx1 target in the regulation of ? -cell mass and function. We will also determine the importance of a target in the endosomal pathway to ? -cell function, including insulin secretion, replication/survival, mitochondrial function, and regulation of autophagy, that may open a new areas for future research.
This proposal will focus on discovering the role of Clec16a (KIAA0350), a gene recently identified to be associated with type 1 diabetes in humans. We know very little of the function of this gene in the insulin producing ? -cells of the pancreas. We are unsure if loss of this gene leads the ? -cells to die or not produce insulin properly. Therefore, our mission is to critically study this gene in order to understand how this gene affects the ?-cell with hopes that our findings will direct future approaches to treat diabetes.
