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

项目摘要/摘要-2型糖尿病(T2D)现已在世界范围内达到流行水平。在.期间 糖尿病前期，血糖升高和心血管后果的风险，如中风、心肌梗死 脑梗塞和死亡率已经增加了2-4倍。尽管如此，仍有一个根本性的差距 了解糖尿病前期是如何发展的以及为什么会发展。停止或逆转T2D发展的战略需要 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，并在骨骼肌(SKM)中从循环中摄取/清除葡萄糖。因素 与这两个过程中的失败有关的治疗被认为是最佳的治疗目标。我们已经确认了p21- 激活的激酶，即PAK1，作为这样一个因子；它是β细胞和SKM中的信号中枢，协调 多方面的葡萄糖动态平衡。PAK1在T2D方面存在缺陷，暗示其缺失可能是一道“拦路虎” 这阻止了T2D中的正常信令。要克服PAK1缺乏症的障碍，我们需要了解 β细胞和SKM中PAK1与其功能的联系机制。我们的长期目标是了解β-CELL是如何 而SKM信号可以被操纵来预防或逆转糖尿病前期并阻止向T2D的进展。我们的 中心假说是1)通过β细胞中的PAK1Hub的信号控制功能的β细胞团 逆转HFD诱导葡萄糖耐量异常，2)SKM中的PAK1信号提供胰岛素保护 抵抗并参与组织串扰，以增强β细胞功能。建议进行这项研究的理由是 一旦阐明了PAK1效应器的这些新机制，就从PAK1中选择信号通路 可以操纵集线器来防止或反转T2D。在上一个资金周期中，我们透露，恢复 T2D人胰岛β细胞中的PAK1逆转胰岛素分泌障碍，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的增加对HFD诱导的葡萄糖具有保护作用 不耐受，并参与组织串扰以改善β细胞功能。我们具有挑衅性的新初步数据 还可以指出哪些PAK1效应器执行这些基本功能。因此，此应用程序的目标是 是为了测试这些候选机制，将PAK1效应器的丰富和保护β细胞和SKM 糖尿病应激，并评估候选PAK1效应物强化疗法。我们会利用我们的诱惑力 用于这些研究的特定组织的小鼠模型和人类组织/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效应器保护PAK1的机制(S β-细胞团；在目标3中，我们将辨别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关于这些PAK1的新假说 在希望之城注重翻译的机构环境中的执行者行动。这项工作将 通过评估有望逆转糖尿病前期和糖尿病前期的候选策略，积极影响糖尿病研究 通过发现葡萄糖内稳态的新机制来阻止向T2D的进展。

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.