Functional studies of the novel diabetes gene TCF19

新型糖尿病基因TCF19的功能研究

• 批准号: 10266092
• 负责人: Dawn B Davis
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266092
• 关键词: Affect; Aging; Alleles; Amputation; Apoptosis; Beta Cell; Blindness; Blood Glucose; Cell Count; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Stress; Cellular Structures; Cellular biology; Code; DNA Damage; DNA Repair; Data; Defect; Dependence; Development; Diabetes Mellitus; Diabetes prevention; Diagnosis; Dialysis procedure; Disease Progression; Ensure; Environment; Failure; Gene Expression; General Population; Genes; Genetic; Genetic Transcription; Genetic study; Genotype; Goals; Growth; Healthcare; Human; Human Cell Line; Ice; Impairment; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney Diseases; Knock-out; Knockout Mice; Knowledge; Lead; Longevity; Mission; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Obese Mice; Obesity; Pancreas; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Population; Predisposition; Prevention; Process; Production; Proteins; Proteomics; Regulation; Research; Risk; Role; Site-Directed Mutagenesis; Stress; Structure of beta Cell of islet; Susceptibility Gene; Testing; Therapeutic; Variant; Veterans; Work; base; biological adaptation to stress; cell growth; diabetes mellitus therapy; diabetes pathogenesis; diabetes risk; diabetogenic; fasting glucose; gene function; genetic predictors; genome wide association study; high risk; human disease; innovation; insight; insulin secretion; islet; knock-down; knockout animal; mouse model; novel; obesity development; obesity genetics; overexpression; preservation; prevent; programs; repaired; response; targeted treatment; treatment strategy

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.

糖尿病不成比例地影响退伍军人，近25%的退伍军人患者被诊断患有糖尿病。减少 功能性胰岛β细胞团在1型和2型糖尿病的发病机制中是共同的。因此，识别 对肿瘤细胞生长和存活至关重要的因子将满足预防和治疗肿瘤的关键治疗需求， 糖尿病的治疗TCF 19是一个新的基因，与1型和2型糖尿病都有关联。 该基因的功能在很大程度上是未知的，但我们的工作表明，它在调节乳腺癌细胞增殖中很重要。 细胞应激途径和细胞凋亡。我们认为TCF 19是正常的细胞适应所必需的 在糖尿病和肥胖症中，它在多种细胞作用中发挥作用，影响增殖和存活。具体- 从理论上讲，我们已经确定了TCF 19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重要成分，可能抑制增殖和存活。很长的- 我的研究计划的长期目标是确定导致糖尿病易感性的新的β细胞因子。 这项提案的目的是确定新的糖尿病基因TCF 19的作用机制， 对糖尿病易感性的影响核心假设是TCF 19在肿瘤细胞增殖、DNA合成和细胞凋亡中起关键作用。 损伤反应和存活，以及TCF 19的功能变化损害了这些过程，并导致发育， 糖尿病的发展为实现这一目标，提出了三个具体目标。在目标1中，我们将确定 Tcf 19基因敲除对小鼠模型中β细胞质量影响。我们将使用一个完整的身体和一个特定的细胞 Tcf 19基因敲除小鼠模型，以确定Tcf 19在衰老和肥胖期间预防糖尿病的必要性 通过其在细胞应激下的细胞扩增和存活中的作用。在目标2中，我们将确定TCF 19在以下方面的作用： 调节应激反应途径以促进胰岛细胞存活。这项工作将在敲除小鼠中进行 胰岛和人胰岛中以确保翻译相关性。在目标3中，我们将确定功能的影响 使用基于遗传和蛋白质的靶向定点突变， 组学数据。总之，这些目标将确定新的糖尿病基因TCF 19在胰岛细胞增殖中的作用， DNA损伤反应、生存和糖尿病易感性。这项创新的研究使用了两种小鼠模型 以及人类胰岛研究，以揭示在胰岛细胞生物学中基本上未被表征的基因TCF 19的功能。 在糖尿病的早期发病过程中。这一贡献是重要的，因为它将推进知识的细胞 适应和澄清这种新的糖尿病基因的功能作用。