Targeting an atypical signaling hub to restore and protect whole body glucose homeostasis

针对非典型信号中枢恢复和保护全身葡萄糖稳态

• 批准号: 10395891
• 负责人: Debbie C Thurmond
• 金额: $ 4.39万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395891
• 关键词: Acute; Apoptosis; Beta Cell; Blood Circulation; Blood Glucose; Cell model; Cell physiology; Cell surface; Cells; Cities; Data; Defect; Development; Diabetes Mellitus; Diet; Disease; Environment; Epidemic; Event; Exposure to; F-Actin; Failure; Fasting; Fatty acid glycerol esters; Functional disorder; Funding; GLUT 4 protein; Glucose; Glucose Intolerance; Goals; Health; Human; Hyperglycemia; Insulin; Insulin Resistance; Intake; Intervention; Knock-out; Knockout Mice; Knowledge; Link; Mechanics; Mediating; Mission; Mitochondria; Molecular; Mus; Muscle Fibers; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathway interactions; Peripheral; Population; Prediabetes syndrome; Predisposition; Prevention; Process; Protein Kinase; Proteins; Public Health; Research; Research Proposals; Role; Sampling; Secretory Cell; Signal Pathway; Signal Transduction; Skeletal Muscle; Stimulus; Stress; Stroke; Structure; Structure of beta Cell of islet; Testing; Therapeutic; Tissues; Translations; Vesicle; Work; base; blood glucose regulation; cardiovascular risk factor; cell type; diabetogenic; glucose uptake; human tissue; impaired glucose tolerance; improved; in vivo; innovation; insulin granule; insulin secretion; insulin sensitivity; islet; knock-down; mitochondrial dysfunction; mortality; mouse model; new therapeutic target; novel; p21 activated kinase; prevent; therapeutic target; tool

Project Summary/Abstract – Type 2 diabetes (T2D) has now reached epidemic proportions worldwide. During pre-diabetes, blood sugars rise and the risk of cardiovascular consequences, such as stroke, myocardial infarction and mortality, is already increasing by 2-4-fold. Despite this, there remains a fundamental gap in understanding how and why pre-diabetes develops. Strategies to halt or reverse T2D development require a multi-pronged approach, since the pathophysiology involves both dysfunction in pancreatic β-cell glucose- stimulated insulin release, and in skeletal muscle (skm) glucose uptake/clearance from the circulation. Factors linked to failures in both processes are considered optimal therapeutic targets. We have identified the p21- activated kinase, PAK1, as such a factor; it is a signaling hub in both the β-cells and skm that orchestrates multiple aspects of glucose homeostasis. PAK1 is deficient in T2D, suggesting that its loss may be a “roadblock” that prevents normal signaling in T2D. To overcome the roadblock of PAK1 deficiency, we need to understand the mechanisms linking PAK1 to its functions in β-cells and skm. Our long-term goal is to understand how β-cell and skm signaling can be manipulated to prevent or reverse pre-diabetes and halt the progression to T2D. Our central hypothesis is that 1) signaling through the PAK1 hub in the β-cell controls functional β-cell mass to reverse HFD-induced glucose intolerance, and that 2) PAK1 signals in skm confer protection from insulin resistance and engage in tissue crosstalk to enhance β-cell function. The rationale for the proposed research is that once these new mechanisms of the PAK1 effectors are elucidated, select signaling pathways from the PAK1 hub can be manipulated to prevent or reverse T2D. During the last funding cycle, we revealed that restoring PAK1 in T2D human islet β-cells reverses dysfunctional insulin secretion while reducing β-cell mitochondrial dysfunction and apoptosis. We also showed that PAK1 enrichment in skm protects against HFD-induced glucose intolerance, and engages in tissue crosstalk to improve β-cell function. Our provocative new preliminary data also indicate which PAK1 effectors carry out these essential functions. Therefore, the objective of this application is to test these candidate mechanisms linking PAK1 effector enrichment and protection of β-cells and skm from diabetogenic stress and to evaluate candidate PAK1 effector enrichment therapeutics. We will use our inducible tissue-specific mouse models and human tissues/cells for these studies. In Aim 1, we will identify how the PAK1 effectors restore β-cell function; in Aim 2, we will elucidate the mechanism(s) by which PAK1-effectors protect β-cell mass; in Aim 3, we will discern the mechanisms by which skm PAK1 contributes to peripheral insulin sensitivity and β-cell health. We will use innovative molecular tools to test novel hypotheses about these PAK1 effector actions in the context of a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a promising candidate strategy to reverse pre-diabetes and halt progression to T2D and by uncovering novel mechanisms of glucose homeostasis.

项目摘要/摘要 - 2型糖尿病（T2D）现已在全球范围内达到流行比例。期间 糖尿病前，血糖升高和心血管后果的风险，例如中风，心肌 梗塞和死亡率已经增加了2-4倍。尽管如此，仍然存在根本的差距 了解糖尿病前期发展的方式。停止或反向T2D开发的策略需要 多沟的方法，因为病理生理学涉及胰腺β细胞葡萄糖的功能障碍 从循环中刺激胰岛素释放，以及骨骼肌（SKM）葡萄糖摄取/清除率。因素 与两个过程中的失败有关的链接被认为是最佳的治疗靶标。我们已经确定了P21- 激活的激酶Pak1是这样的因素；它是β细胞和SKM的信号枢纽 葡萄糖稳态的多个方面。 PAK1缺乏T2D，表明其损失可能是“障碍” 这可以防止T2D中的正常信号传导。为了克服PAK1缺乏症的障碍，我们需要了解 将PAK1与其在β细胞和SKM中的功能联系起来的机制。我们的长期目标是了解β细胞如何 可以操纵SKM信号传导以防止或反向糖尿病前，并停止发展为T2D。我们的 中心假设是1）通过β细胞中PAK1中心的信号传导控制功能性β细胞质量 反向HFD诱导的葡萄糖intlerance，以及2）SKM中的PAK1信号允许保护免受胰岛素的保护 阻力并参与组织串扰以增强β细胞功能。拟议研究的理由是 一旦阐明了PAK1效应器的这些新机制，请从PAK1中选择信号通路 可以操纵轮毂以防止或反向T2D。在最后一个资金周期中，我们透露了还原 T2D人类胰岛β细胞中的PAK1逆转功能失调的胰岛素分泌，同时还原β细胞线粒体 功能障碍和凋亡。我们还表明，SKM中的PAK1富集可以防止HFD诱导的葡萄糖 intlerance，并参与组织串扰以改善β细胞功能。我们挑衅的新初步数据 还指示哪些PAK1效应器执行这些基本功能。因此，此应用程序的目的 是测试这些候选机制，这些机制将pak1效应器富集和保护β细胞和SKM的保护 糖尿病性压力并评估候选PAK1效应富集疗法。我们将使用我们的诱导 这些研究的组织特异性小鼠模型和人体组织/细胞。在AIM 1中，我们将确定PAK1如何 生效恢复β细胞功能；在AIM 2中，我们将阐明PAK1-EFFECTORS保护的机制 β细胞质量；在AIM 3中，我们将辨别SKM PAK1有助于周围胰岛素的机​​制 灵敏度和β细胞健康。我们将使用创新的分子工具来测试有关这些PAK1的新假设 效应子在希望之城以翻译为重点的机构环境的背景下。这项工作将 通过评估有承诺的候选策略来扭转糖尿病前的候选策略，从而对糖尿病的研究产生积极影响 停止向T2D的进展，并发现葡萄糖稳态的新机制。