Functional studies of the novel diabetes gene TCF19

新型糖尿病基因TCF19的功能研究

• 批准号: 9976984
• 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/9976984
• 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.

糖尿病对退伍军人的影响尤为严重，近25%的退伍军人被诊断患有糖尿病。减少