Role of SIRT7 in the Pancreatic Beta Cells

SIRT7 在胰腺 β 细胞中的作用

• 批准号: 10584580
• 负责人: Zong Wei
• 金额: $ 41.41万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584580
• 关键词: Anti-Inflammatory Agents; Antidiabetic Drugs; Apoptotic; B-Lymphocytes; Beta Cell; Biological Assay; Cell Line; Cell physiology; Cells; Cellular Stress; Chromatin; Clinical; Collaborations; Deacetylase; Deacetylation; Development; Diabetes Mellitus; Diabetic mouse; Elements; Enhancers; Epidemic; Epigenetic Process; Failure; Family member; Functional disorder; Genes; Genetic; Genetic Transcription; Glucose; Goals; High Fat Diet; Histone Deacetylase; Histones; Human; Hyperactivity; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin; Knock-out; Knockout Mice; Mediating; Metabolic stress; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Overnutrition; Pathogenesis; Pathway interactions; Phenocopy; Physiological; Predisposition; Prevalence; Receptor Signaling; Regulatory Element; Repression; Role; Signal Transduction; Sirtuins; Specificity; Streptozocin; Stress; Structure of beta Cell of islet; Testing; Vitamin D; Vitamin D3 Receptor; biological adaptation to stress; diabetes mellitus therapy; diabetes pathogenesis; driving force; epigenetic profiling; epigenetic regulation; epigenome; gene induction/repression; genetic corepressor; genome-wide; global health; glucose metabolism; histone modification; in vivo; in vivo Model; insight; insulin secretion; islet; loss of function; mouse model; mutant; next generation; novel; novel strategies; pharmacologic; prevent; promoter; recruit; synergism; therapeutic evaluation; transcription factor; transcriptome; transcriptome sequencing

Project Summary β cell dysfunction is critical for the pathogenesis of type 2 diabetes mellitus (T2DM). Studies suggested that over-nutrition and inflammation induce profound changes in the transcriptome and the epigenome of beta cells, resulting in impaired glucose-stimulated insulin secretion, and loss of beta cell mass. However, the molecular mechanisms of the epigenetic regulation in beta cell function and failure remain largely unclear. Our recent results suggest that SIRT7, a NAD+-dependent deacetylase, regulate the glucose-stimulated insulin secretion (GSIS), and antagonize inflammation- and overnutrition-induced islet dysfunction. We found that SIRT7 activates the expression of a number of key genes in the insulin synthesis and secretion pathways, while suppresses the inflammatory and metabolic stress-induced transcription. These results raise the possibility that SIRT7 simultaneously activates GSIS pathway, and represses stress-induced inflammatory responses, through diverge molecular mechanisms. SIRT7 interacts with PBRM1, a chromatin remodeler, which controls the chromatin accessibility of regulatory cis-elements associated with the GSIS pathway genes. On the other hand, SIRT7 deacetylates H3K18Ac, a histone marks highly enriched in stress-induced promoter/enhancers in beta cells. In addition, the ability and specificity of SIRT7 to repress targets is regulated by the intracellular level of NAD+, and its interacting partner, vitamin D receptor (VDR), respectively. We hypothesize that SIRT7 is an essential regulator of insulin secretion and stress responses in beta cells through integrating NAD+ and vitamin D signaling at the chromatin level. Accordingly, Specific Aim 1 will utilize novel genetic loss-of-function mouse models to test the hypothesis that SIRT7 promotes insulin secretion through recruiting PBRM1 and maintaining the chromatin accessibility. Specific Aim 2 will use multiple diabetes mouse models, to determine the molecular underpinnings of SIRT7 in antagonizing stress-induced transcription in beta cells, through deacetylating H3K18Ac and acting as a novel co-repressor of VDR. Lastly, Aim 3 will dissect the converge of NAD+-SIRT7 and vitamin D-VDR signaling at the chromatin level, and test the therapeutic potential of co- activating SIRT7-VDR to antagonize both mouse and human islet dysfunction. The proposed project will reveal novel molecular regulatory mechanisms of beta cell function in healthy and dysfunctional state and may lead to novel strategies for the development of next generation anti-diabetic therapies directly targeting β cell dysfunction.

项目摘要 β细胞功能障碍是2型糖尿病（T2 DM）发病的关键。研究表明 营养过剩和炎症诱导β细胞的转录组和表观基因组的深刻变化， 导致葡萄糖刺激的胰岛素分泌受损和β细胞质量损失。然而，分子 β细胞功能和衰竭中的表观遗传调节机制仍然很不清楚。我们最近 结果表明，SIRT 7，NAD+依赖性脱乙酰酶，调节葡萄糖刺激的胰岛素分泌 （GSIS），并拮抗炎症和营养过度诱导的胰岛功能障碍。我们发现SIRT 7 激活胰岛素合成和分泌途径中许多关键基因的表达， 抑制炎症和代谢应激诱导的转录。这些结果提出了一种可能性， SIRT 7同时激活GSIS通路，并抑制应激诱导的炎症反应， 通过不同的分子机制。SIRT 7与PBRM 1相互作用，PBRM 1是一种染色质重塑剂， 与GSIS途径基因相关的调控顺式元件的染色质可及性。另 另一方面，SIRT 7使H3 K18 Ac去乙酰化，H3 K18 Ac是一种在应激诱导的启动子/增强子中高度富集的组蛋白标记， β细胞此外，SIRT 7抑制靶点的能力和特异性受细胞内信号转导通路的调节。 NAD+及其相互作用伴侣维生素D受体（VDR）水平。我们假设SIRT 7 是β细胞中胰岛素分泌和应激反应的重要调节剂，通过整合NAD+和 维生素D信号在染色质水平。因此，具体目标1将利用新的遗传功能丧失， 小鼠模型，以检验SIRT 7通过募集PBRM 1促进胰岛素分泌的假设， 保持染色质可接近性。具体目标2将使用多种糖尿病小鼠模型，以确定 SIRT 7拮抗β细胞中应激诱导的转录的分子基础， 使H3 K18 Ac脱乙酰化并作为VDR的新型共阻遏物。最后，目标3将剖析 NAD+-SIRT 7和维生素D-VDR信号转导在染色质水平，并测试治疗潜力的共 激活SIRT 7-VDR以拮抗小鼠和人胰岛功能障碍。该项目将揭示 在健康和功能障碍状态下β细胞功能的新分子调节机制，并可能导致 开发直接靶向β细胞的下一代抗糖尿病疗法的新策略 功能障碍