Functional studies of the novel diabetes gene TCF19

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Diabetes disproportionately affects Veterans, with nearly 25% of VA patients diagnosed with diabetes. Reduced functional -cell mass is common to the pathogenesis of both type 1 and type 2 diabetes. Therefore, identifying factors that are critical for -cell growth and survival will meet a critical therapeutic need in the prevention and treatment of diabetes. TCF19 is a novel gene that has been associated with both type 1 and type 2 diabetes. The function of this gene is largely unknown, but our work has shown it is important in regulation of -cell prolif- eration, cell stress pathways and apoptosis. We propose that TCF19 is necessary for normal -cell adaptation in diabetes and obesity, and that it functions in multiple cellular roles to impact proliferation and survival. Specif- ically, we have identified a unique role for TCF19 in DNA damage pathways and show that DNA damage is an important component of cell stress in diabetes and obesity that may inhibit proliferation and survival. The long- term goal of my research program is to identify the novel -cell factors that contribute to diabetes susceptibility. The objective of this proposal is to identify the mechanism whereby the novel diabetes gene, TCF19, contributes to diabetes susceptibility. The central hypothesis is that TCF19 plays a critical role in -cell proliferation, DNA damage response and survival, and functional changes in TCF19 impair these processes and lead to the devel- opment of diabetes. To achieve the objective, three Specific Aims are proposed. In Aim 1, we will determine the impact of Tcf19 knockout on -cell mass in mouse models. We will use both a whole body and a -cell specific Tcf19 knockout mouse model to determine the necessity of Tcf19 to prevent diabetes during aging and in obesity via its role in -cell expansion and survival under cell stress. In Aim 2, we will determine the role of TCF19 in regulation of stress response pathways to promote -cell survival. This work will be performed in knockout mouse islet and in human islets to ensure translational relevance. In Aim 3, we will identify the impact of functional variants on the role of TCF19 in the -cell using targeted site-directed mutagenesis based on genetic and prote- omics data. Together, these aims will identify the role of the novel diabetes gene, TCF19, in -cell proliferation, DNA damage responses, survival and diabetes susceptibility. This innovative research uses both mouse models and human islet studies to uncover the function of the largely uncharacterized gene TCF19 in -cell biology during the early pathogenesis of diabetes. This contribution is significant as it will advance knowledge of -cell adaptation and clarify the functional role of this novel diabetes gene.