ROCK1 Signaling in Glucose Metabolism

葡萄糖代谢中的 ROCK1 信号传导

• 批准号: 7783165
• 负责人: YOUNG-BUM KIM
• 金额: $ 37.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783165
• 关键词: Ablation; Actins; Adenoviruses; Adipocytes; Adipose tissue; Affect; Biochemical; Biological Process; Breeding; Cell Line; Cells; Data; Diabetes Mellitus; Diabetic mouse; Gene Targeting; Gene Transfer; Goals; Grant; Human; Insulin; Insulin Resistance; Lead; Mediating; Mediator of activation protein; Metabolic; Metabolism; Molecular; Mus; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Protein Isoforms; RNA Interference; ROCK1 gene; Regulation; Rho-associated kinase; Risk Factors; Role; Serine; Signal Transduction; Skeletal Muscle; Small RNA; Tissues; Work; adiponectin; base; blood glucose regulation; glucose metabolism; glucose tolerance; glucose transport; glucose uptake; in vivo; insulin sensitivity; insulin signaling; mutant; novel; prevent; public health relevance; recombinase; research study; response

DESCRIPTION (provided by applicant): We have identified Rho-Kinase (ROCK) as a novel regulator of insulin action and glucose homeostasis. Specifically, ROCK directly regulates IRS-1 function by phosphorylating serine residues. Inhibition of ROCK function results in a reduction of insulin-stimulated glucose transport and insulin signaling, leading to insulin resistance. We found that ROCK1 deficiency causes systemic insulin resistance in vivo by impairing insulin signaling in skeletal muscle. Furthermore, insulin-stimulated ROCK activity is decreased in the skeletal muscle of obese diabetic mice and humans, suggesting that defective ROCK activity may contribute to the pathogenesis of insulin resistance. We thus hypothesize that activation of ROCK1 is critical for the metabolic action of insulin on glucose transport and insulin signaling through IRS-1 serine phosphorylation. The overall objective of this proposal is to define the novel role of ROCK1 in the regulation of glucose metabolism and insulin signaling. Aim 1 works to determine the role of IRS-1 serine phosphorylation in ROCK1-dependent glucose metabolism. We will systemically investigate how ROCK1 controls insulin- mediated glucose metabolism via affecting IRS-1 serine phosphorylation. This will be achieved by reintroducing IRS-1 mutants in IRS-1-deficient cells and mice. Aim 2 further elucidates the molecular mechanism in which ROCK1 is a key regulator of insulin action on glucose transport and downstream signaling. We will use small RNA interference and adenovirus gene-transfer strategies to determine the fundamental basis underlying insulin-induced activation of ROCK1 in insulin-sensitive cells or specific cell lines in which ROCK1 or IRS-1 has been deleted. Aim 3 defines the role of ROCK1 in whole-body glucose homeostasis and insulin sensitivity in insulin-target tissues. We have successfully generated loxP flanked ROCK1 mice, which are currently being breed with mice expressing MCK-Cre or adiponectin-Cre recombinase producing muscle- or adipose-specific ROCK1-deficient mice. These mice will be characterized for whole-body insulin sensitivity and glucose homeostasis, with important implications for strategies to prevent diabetes. These studies provide a unique opportunity to identify a novel molecular mechanism in which ROCK1 is important as a critical node in insulin control of metabolism, and may offer a novel target for the treatment of diabetes and obesity. PUBLIC HEALTH RELEVANCE: Insulin resistance is a major risk factor for type 2 diabetes, and the cause of this is not fully understood. Preliminary data show that the inhibition of the ROCK1 function results in a decreased insulin response, leading to insulin resistance. The goal of the study is to determine the biological function of ROCK1 in insulin control of glucose metabolism, and these experiments could lead to the identification of a potential target for new diabetes drugs.

描述（由申请人提供）：我们已经将Rho-kinase（Rock）确定为胰岛素作用和葡萄糖稳态的新型调节剂。具体而言，岩石通过磷酸化丝氨酸残基直接调节IRS-1功能。岩石功能的抑制导致胰岛素刺激的葡萄糖转运和胰岛素信号的降低，从而导致胰岛素抵抗。我们发现，岩石1缺乏通过损害骨骼肌中的胰岛素信号传导而导致全身性胰岛素耐药性。此外，在肥胖的糖尿病小鼠和人类的骨骼肌中，胰岛素刺激的岩石活性降低，这表明有缺陷的岩石活性可能有助于胰岛素抵抗的发病机理。因此，我们假设Rock1的激活对于通过IRS-1丝氨酸磷酸化对胰岛素对葡萄糖转运和胰岛素信号传导的代谢作用至关重要。该提案的总体目的是定义Rock1在调节葡萄糖代谢和胰岛素信号传导调节中的新作用。 AIM 1努力确定IRS-1丝氨酸磷酸化在岩石1依赖性葡萄糖代谢中的作用。我们将系统地研究Rock1如何通过影响IRS-1丝氨酸磷酸化来控制胰岛素介导的葡萄糖代谢。这将通过在IRS-1缺陷型细胞和小鼠中重新引入IRS-1突变体来实现。 AIM 2进一步阐明了Rock1是胰岛素作用对葡萄糖转运和下游信号传导的关键调节剂的分子机制。我们将使用小的RNA干扰和腺病毒基因转移策略来确定胰岛素敏感细胞中胰岛素诱导的Rock1的基本基础或已删除Rock1或IRS-1的特定细胞系的基本基础。 AIM 3定义了Rock1在全身葡萄糖稳态中的作用和胰岛素靶向组织中的胰岛素敏感性。我们已经成功产生了LOXP侧翼岩石小鼠，目前正在繁殖MICE，表达MCK-CRE或脂联蛋白 - CRE重组酶产生肌肉或脂肪特异性岩石1缺陷小鼠。这些小鼠的特征是全身胰岛素敏感性和葡萄糖稳态，对预防糖尿病的策略具有重要意义。这些研究提供了一个独特的机会来识别一种新型的分子机制，在该机制中，Rock1在代谢的胰岛素控制中很重要，并且可能为治疗糖尿病和肥胖症的治疗提供了新的靶标。 公共卫生相关性：胰岛素抵抗是2型糖尿病的主要危险因素，原因尚未完全理解。初步数据表明，对Rock1功能的抑制会导致胰岛素反应降低，从而导致胰岛素抵抗。该研究的目的是确定Rock1在葡萄糖代谢的胰岛素控制中的生物学功能，这些实验可能导致鉴定新糖尿病药物的潜在靶标。