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细胞功能障碍对于2型糖尿病（T2DM）的发病机理至关重要。研究表明 过度营政和炎症会导致转录组和β细胞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细胞量的损失。但是，分子 β细胞功能和失效中表观遗传调节的机制在很大程度上仍不清楚。我们的最新消息 结果表明SIRT7是NAD+依赖性脱乙酰基酶，调节葡萄糖刺激的胰岛素分泌 （GSIS），并拮抗注射和肢体诱导的胰岛功能障碍。我们发现Sirt7 激活胰岛素合成和分泌途径中许多关键基因的表达，而 抑制炎症和代谢应激诱导的转录。这些结果增加了可能性 SIRT7只是激活GSIS途径，并反映压力诱导的炎症反应，即 通过分子机制进行分解。 SIRT7与PBRM1（控制的染色质重塑剂）相互作用 与GSIS途径基因相关的调节顺式元件的染色质可及性。另一方面 手，SIRT7脱乙酰基H3K18AC，Hisstone标记在压力诱导的启动子/增强子中高度富集 β细胞。另外，SIRT7反映目标的能力和特异性受细胞内调节 NAD+的水平及其相互作用的伴侣分别是维生素D受体（VDR）。我们假设Sirt7 是通过整合NAD+和 维生素D信号在染色质水平上。彼此之间，特定的目标1将利用新的遗传功能丧失 小鼠模型测试了SIRT7通过募集PBRM1和 保持染色质的可及性。特定目标2将使用多个糖尿病小鼠模型来确定 SIRT7在拮抗β细胞中拮抗应激诱导的转录的分子基础，通过 脱乙酰化H3K18AC并充当VDR的新型共抑制剂。最后，AIM 3将剖析 NAD+-SIRT7和维生素D-VDR信号在染色质水平上，并测试共同的治疗潜力 激活SIRT7-VDR以拮抗小鼠和人类胰岛功能障碍。拟议的项目将揭示 健康和功能障碍状态下β细胞功能的新型分子调节机制，可能导致 直接针对β细胞的下一代抗糖尿病疗法开发的新策略 功能障碍。