Functional studies of the novel diabetes gene TCF19

糖尿病对退伍军人的影响不成比例，近25%的退伍军人退伍军人被诊断为糖尿病。减少 功能性细胞团是1型和2型糖尿病共同的发病机制。因此，识别 对-细胞生长和存活至关重要的因素将满足预防和治疗的关键需要 糖尿病的治疗。TCF19是一个与1型和2型糖尿病相关的新基因。 这个基因的功能在很大程度上还不清楚，但我们的工作表明，它在调节细胞的增殖方面很重要。 信号转导、细胞应激途径和细胞凋亡。我们认为TCF19是正常的细胞适应所必需的 在糖尿病和肥胖症中，它在多种细胞中发挥作用，影响增殖和生存。指定- 从技术上讲，我们已经确定了TCF19在DNA损伤途径中的独特作用，并表明DNA损伤是一种 糖尿病和肥胖症中细胞应激的重要组成部分，可能抑制细胞增殖和存活。长的- 我的研究计划的学期目标是确定导致糖尿病易感性的新的细胞因子。 这项建议的目的是确定新的糖尿病基因TCF19的作用机制 对糖尿病的易感性。中心假设是TCF19在细胞的增殖中起关键作用。 损伤反应和存活，以及TCF19的功能变化破坏了这些过程，导致了TCF19的发展。 糖尿病的进展。为了实现这一目标，提出了三个具体目标。在目标1中，我们将确定 TCF19基因敲除对小鼠细胞质量的影响我们将同时使用全身和细胞特异性 Tcf19基因敲除小鼠模型确定Tcf19在预防糖尿病衰老和肥胖中的必要性 通过其在-细胞扩增和细胞应激下的存活中的作用。在目标2中，我们将确定TCF19在 调节应激反应通路以促进-细胞存活。这项工作将在基因敲除小鼠中进行 小岛和人类小岛，以确保翻译相关性。在目标3中，我们将确定功能 利用基于基因和蛋白的定点突变技术研究TCF19在细胞中的作用 组学数据。总之，这些目标将确定新的糖尿病基因TCF19在细胞增殖中的作用， DNA损伤反应、存活率和糖尿病易感性。这项创新性的研究使用了两种小鼠模型 人类胰岛研究揭示了细胞生物学中基本上未描述的基因TCF19的功能 在糖尿病的早期发病机制中。这一贡献意义重大，因为它将促进对-CELL的了解 并阐明这一新的糖尿病基因的功能作用。

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.