Targeting PAK1 to improve functional beta-cell mass and insulin sensitivity

靶向 PAK1 以改善功能性 β 细胞质量和胰岛素敏感性

• 批准号: 8815580
• 负责人: Debbie C Thurmond
• 金额: $ 34.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815580
• 关键词: Actins; Acute; Am 80; Apoptosis; Beta Cell; Biochemical; Biological Assay; Biological Preservation; Biosensor; Blood Glucose; Cardiovascular system; Cell Survival; Cell membrane; Cell physiology; Cell surface; Cells; Cytoskeleton; Data; Defect; Development; Diabetes Mellitus; Diet; Disease; Docking; Employee Strikes; Event; Exocytosis; Exposure to; F-Actin; Failure; Fasting; Fatty acid glycerol esters; Functional disorder; GLUT4 gene; Genetic; Glucose; Glucose Intolerance; Goals; Health; Human; Hyperglycemia; Insulin; Insulin Resistance; Intake; Intervention; Knock-out; Knockout Mice; Knowledge; Life; Link; Mediating; Mission; Molecular; Mus; Muscle; Muscle Fibers; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pancreas; Pathway interactions; Peripheral; Play; Population; Prediabetes syndrome; Predisposition; Prevention; Process; Proteins; Public Health; Reporting; Research; Risk Factors; Role; SNAP receptor; Signal Transduction; Skeletal Muscle; Stimulus; Stroke; Testing; Therapeutic; Tissues; Vesicle; Work; base; blood glucose regulation; cell type; cellular imaging; diabetic; feeding; glucose uptake; impaired glucose tolerance; improved; in vivo; innovation; insulin granule; insulin secretion; insulin sensitivity; islet; mortality; new therapeutic target; p21 activated kinase; prevent; restoration; scaffold

DESCRIPTION (provided by applicant): As blood sugars rise during development of pre-diabetes, cardiovascular consequences such as stroke, myocardial infarction and mortality are already increasing by 2-4 fold, yet there remains a fundamental gap in understanding how and why pre-diabetes develops. The inability to predict, within a population with similar risk factors for diabetes, which are more susceptible than others represents an important problem because, until it is resolved, strategies to prevent/treat pre-diabetes/dysglycemia will remain largely untenable. Strategies to halt dysglycemia require a multi-pronged approach, since the pathophysiology involves both peripheral insulin resistance and pancreatic β cell dysfunction. Factors that are linked to failures in both processes are in-demand for therapeutic focus; we have identified the p21-activated kinase, PAK1, as such a factor. Further, losses of PAK1 abundance are associated with diabetes and obesity in human islets and human skeletal muscle, tissues that are key to regulating insulin release and insulin sensitivity, respectively. Thus, the long-term goal is to understand how the PAK1 pathways in these tissues can be manipulated to treat/prevent pre-diabetes, ultimately halting progression to frank diabetes. The objective of this particular application is to discriminate how PAK1 functions (PAK1 plays roles in signaling as well as scaffolding in other cell types) in β cell insulin secretion and skeletal muscle insulin action in vivo and at the molecular level. PAK1 pathways are known in other cell types to evoke dynamic actin cytoskeleton changes, and preliminary data suggest such changes to be part of insulin release and glucose clearance mechanisms. Preliminary data show that classic whole-body PAK1 knockout mice fed a 42% fat diet for just 10 weeks develop fasting hyperglycemia, insulin insufficiency and severe glucose intolerance. Additionally, restoration of PAK1 abundance or signaling in islet β cells restores insulin secretion and reduces β cell apoptosis. These findings give rise to the central hypotheses, that a) PAK1 is a central regulator of glucose homeostasis via functions in actin remodeling-regulated exocytosis events in both β cells and skeletal muscle cells, and b) that PAK1 deficiency culminates in heightened susceptibility to glycemic dysregulation and pre-diabetes. The rationale for the proposed research is that once it is known how PAK1 is needed in β cells versus skeletal muscle cells, that the PAK1 pathways can be manipulated to avert pre-diabetic dysglycemia. This hypothesis will be tested in two Specific Aims: 1) Delineate the mechanism(s) for PAK1 actions in β cell function and survival, 2) Elucidate the mechanism(s) by which PAK1 promotes skeletal muscle insulin sensitivity. Aims will be accomplished using innovative inducible β cell and skeletal muscle PAK1 knockout mice and live-cell imaging biosensors with biochemical assays, and relevant human islet and muscle tissues. Results of these interrogations are expected to positively impact efforts to ameliorate pre-diabetes, because the identified effectors and mechanisms are highly likely to provide new therapeutic targets.

描述（由适用提供）：随着糖尿病前期的血糖的增加，诸如中风，心肌梗塞和死亡率之类的心血管后果已经增加了2-4倍，但是在理解糖尿病前期糖尿病前期以及为什么发展的基本差距仍然存在。无法预测具有类似糖尿病风险因素的人群中，比其他糖尿病更容易受到影响，这是一个重要的问题，因为在解决问题之前，预防/治疗糖尿病前/糖尿病前/糖糖症的策略将在很大程度上站不住脚。停止血糖的策略需要多管齐下的方法，因为病理生理学涉及外周胰岛素抵抗和胰腺β细胞功能障碍。与这两个过程中失败有关的因素都是治疗重点的需求。我们已经将P21激活的激酶Pak1确定为这样的因素。此外，PAK1抽象的损失与人类胰岛和人骨骼肌的糖尿病和肥胖有关，这是调节胰岛素释放和胰岛素敏感性的关键组织。这就是长期目标是了解如何操纵这些组织中的PAK1途径以治疗/预防糖尿病前，最终停止弗兰克糖尿病的进展。该特定应用的目的是区分β细胞胰岛素分泌和骨骼肌胰岛素在体内和分子水平中如何在其他细胞类型的信号传导以及其他细胞类型的脚手架中的作用（PAK1扮演）。 PAK1途径在其他细胞类型中是已知的，以引起动态肌动蛋白细胞骨架的变化，而初步数据表明，这种变化是胰岛素释放和葡萄糖清除机制的一部分。初步数据表明，经典的全身PAK1基因敲除小鼠仅10周喂养了42％的脂肪饮食，发展了空腹高血糖，胰岛素不足和严重的葡萄糖intlerance。另外，胰岛细胞中PAK1抽象或信号传导的恢复可恢复胰岛素的分泌并减少β细胞凋亡。这些发现引起了核心假设，即a）Pak1是通过肌动蛋白重塑调节调节调节的β细胞和骨骼肌细胞中葡萄糖稳态的中心调节剂，而b）PAK1不足症状在高峰性降低糖症的敏感性和预先降低的敏感性。拟议的研究的基本原理是，一旦知道β细胞与骨骼肌细胞中需要PAK1，可以操纵PAK1途径以避免糖尿病前血糖症。该假设将以两个具体的目的进行检验：1）描述β细胞功能和生存中PAK1作用的机制，2）阐明PAK1促进骨骼肌胰岛素敏感性的机制。将使用创新的诱导β细胞和骨骼肌PAK1基因敲除小鼠以及具有生化测定的活细胞成像生物体以及相关的人类胰岛和肌肉组织来实现目标。这些审讯的结果有望积极影响减轻糖尿病前的努力，因为确定的效果和机制极有可能提供新的治疗靶标。