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: 10311546
• 负责人: Debbie C Thurmond
• 金额: $ 44万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311546
• 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; Persons; 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程度。期间 糖尿病前期，血糖升高以及心血管后果的风险，例如中风、心肌梗塞 梗塞和死亡率已经增加了 2-4 倍。尽管如此，仍存在根本性差距 了解糖尿病前期如何以及为何发生。停止或扭转 T2D 发展的策略需要 多管齐下，因为病理生理学涉及胰腺 β 细胞葡萄糖- 刺激胰岛素释放，以及骨骼肌 (skm) 葡萄糖从循环中的摄取/清除。因素 与这两个过程的失败相关的被认为是最佳治疗目标。我们已经确定了 p21- 激活激酶，PAK1，作为这样的因子；它是 β 细胞和 skm 中的信号中枢，负责协调 葡萄糖稳态的多个方面。 PAK1 在 T2D 中存在缺陷，表明其丢失可能是一个“障碍” 阻止 T2D 中的正常信号传导。为了克服 PAK1 缺陷的障碍，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 信号传导来预防或逆转糖尿病前期并阻止进展为 T2D。我们的 中心假设是 1) 通过 β 细胞中的 PAK1 中枢的信号传导控制功能性 β 细胞群 逆转 HFD 诱导的葡萄糖不耐受，并且 2) skm 中的 PAK1 信号可提供胰岛素保护 抵抗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，就可以从 PAK1 中选择信号通路 可以操纵集线器来预防或逆转 T2D。在上一个融资周期中，我们透露恢复 T2D 人胰岛 β 细胞中的 PAK1 可逆转胰岛素分泌功能障碍，同时减少 β 细胞线粒体 功能障碍和细胞凋亡。我们还表明 skm 中 PAK1 的富集可以防止 HFD 诱导的葡萄糖 不耐受，并参与组织串扰以改善 β 细胞功能。我们具有挑战性的新初步数据 还表明哪些 PAK1 效应器执行这些基本功能。因此，本申请的目的 的目的是测试这些候选机制，将 PAK1 效应子富集与 β 细胞和 skm 的保护联系起来 糖尿病应激并评估候选 PAK1 效应子富集疗法。我们将使用我们的诱导剂 用于这些研究的组织特异性小鼠模型和人体组织/细胞。在目标 1 中，我们将确定 PAK1 如何 效应器恢复β细胞功能；在目标 2 中，我们将阐明 PAK1 效应物保护的机制 β细胞团；在目标 3 中，我们将了解 skm PAK1 对外周胰岛素的贡献机制 敏感性和 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 希望之城以翻译为中心的制度环境中的效应器行动。这项工作将 通过评估有前途的候选策略来逆转糖尿病前期和 阻止进展为 T2D 并揭示葡萄糖稳态的新机制。