Chronic_Kidney_Disease_and_Impaired_Actions_of_Insulin

慢性肾脏疾病和胰岛素作用受损

• 批准号: 9264450
• 负责人: Sandhya S Thomas
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264450
• 关键词: Address; Advisory Committees; Affect; Age; American; Binding; Binding Proteins; Biomedical Research; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiac development; Cellular biology; Chemicals; Chronic Kidney Failure; Complex; Complication; Creatinine; Cytoplasmic Tail; Defect; Development; Diabetes Mellitus; Dialysis patients; Disease; Doppler Echocardiography; Environment; Ethics; Excess Mortality; Exhibits; Fibrosis; Functional disorder; Funding; Goals; Grant; Heart; Heart Diseases; Heart Rate; Immunoglobulin A; Impairment; Inflammation; Inflammatory; Information Systems; Inherited; Insulin; Insulin Receptor; Insulin Resistance; Intracellular Signaling Proteins; Justice; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Lead; Manuscripts; Measures; Mediating; Mediator of activation protein; Membrane; Mentors; Mentorship; Molecular Biology; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscular Atrophy; Mutant Strains Mice; Myoblasts; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Obesity; PTPN11 gene; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Play; Process; Protein Tyrosine Phosphatase; Proteins; Quality of life; Recruitment Activity; Reporting; Research; Research Design; Research Personnel; Role; SHPS-1 protein; Serum; Signal Transduction; Skeletal Muscle; Therapeutic; Translational Research; Tyrosine; Tyrosine Phosphorylation; United States; Veterans; Writing; base; cardiogenesis; career; coronary fibrosis; cytokine; improved; in vivo; inhibitor/antagonist; insulin mediators; insulin receptor substrate 1 protein; insulin signaling; interest; meetings; mortality; muscle form; muscle metabolism; mutant; non-diabetic; novel; prevent; protein expression; protein metabolism; public health relevance; receptor; skeletal muscle wasting; skills; therapy development; wasting

DESCRIPTION (provided by applicant): Fliser et al. identified the presence of insulin resistance in non-diabetic patients with IgA or inherited nephropathies and nearly normal values of serum creatinine and GFR, pointing out that this complication is not restricted to dialysis patients. They concluded that chronic kidney disease (CKD) rather than a specific kidney disease causes insulin resistance. However, mechanisms causing insulin resistance in CKD are unsettled: there appears to be normal binding of insulin to its receptor with the defect present in intracellular signaling. My project i based on a novel pathway I uncovered, namely that CKD stimulates the expression of a membrane- bound, tyrosine phosphatase, Signal Regulatory Protein Alpha (SIRP-alpha), resulting in reduced tyrosine phosphorylation of the insulin receptor and its downstream mediator, insulin receptor substrate-1. My goal is to determine how CKD-stimulated SIRP-alpha induces skeletal muscle wasting and cardiac muscle fibrosis and dysfunction. CKD is a major concern for U.S. Veterans because of the increased morbidity and mortality it invariably causes, including insulin resistance. My long-term goal is to identify mechanisms causing insulin resistance in CKD and to develop therapeutic strategies to prevent its catabolic complications. The development of insulin resistance is not limited to CKD but occurs in obesity, type 2 diabetes and inflammatory conditions and it is tempting to speculate that results of my studies might extend to other conditions. Fortunately, the research interests of my mentors, Drs. Garcia and Mitch, are at least in part similar to my goals while Drs. Chan, Justice & Taegtmeyer can help me address experimental problems. My Preliminary Results indicate that increased SIRP-alpha expression occurs via NF-alphaB and that silencing SIRP-alpha in muscle cells enhances insulin signaling and suppresses protein wasting. Specific Aim 1: to determine whether tyrosine phosphorylation of SIRP-alpha recruits SHP2 and whether the SIRP-alpha-SHP2 complex reduces tyrosine phosphorylation of the insulin receptor and IRS-1. Specific Aim 2: to study the mouse with whole body KO of SIRP-alpha by inducing CKD. My goal is to examine how CKD in the absence of SIRP-alpha affects insulin signaling and muscle metabolism. I will determine how CKD affects muscle metabolism in mice with muscle-specific KO of SIRP-alpha. Specific Aim 3: we also find increased SIRP-alpha expression in hearts of mice with CKD. Since diabetes can cause fibrosis in the heart with impaired function, I plan to determine if SIRP-alpha KO mice are protected against the development of CKD-stimulated cardiac fibrosis and decreased function. My short-term goals are to address these Specific Aims as a prelude to becoming an independently- funded principle investigator. My long term goal is to identify mechanisms causing the complications of impaired insulin signaling and CKD. Specifically, I will enhance my knowledge and skills in didactic courses plus seminars (e.g. cell and molecular biology, grant and manuscript writing, ethics in biomedical research and translational research design). I believe I have the necessary environment to grow into a successful investigator, including strong mentorship, a world-renowned Career Advisory Committee and participation in local and national research meetings. To extend my research, I am applying for the VA-CDA and hope to develop therapies to improve the quality of life of U.S. Veterans, suffering from conditions such as CKD, type 2 diabetes or obesity that are characterized by impaired insulin signaling.

描述（由申请人提供）： 弗莱瑟等人。确定了患有 IgA 或遗传性肾病且血清肌酐和 GFR 值接近正常的非糖尿病患者存在胰岛素抵抗，并指出这种并发症并不限于透析患者。他们得出的结论是，慢性肾病（CKD）而不是特定的肾病会导致胰岛素抵抗。然而，导致 CKD 胰岛素抵抗的机制尚未确定：胰岛素与其受体的结合似乎正常，但细胞内信号传导存在缺陷。我的项目基于我发现的一条新途径，即 CKD 刺激膜结合酪氨酸磷酸酶、信号调节蛋白 Alpha (SIRP-alpha) 的表达，导致胰岛素受体及其下游介质的酪氨酸磷酸化减少，胰岛素受体底物-1。我的目标是确定 CKD 刺激的 SIRP-alpha 如何诱导骨骼肌萎缩以及心肌纤维化和功能障碍。 慢性肾病是美国退伍军人的一个主要担忧，因为它总是会导致发病率和死亡率增加，包括胰岛素抵抗。我的长期目标是确定导致 CKD 胰岛素抵抗的机制，并制定治疗策略来预防其分解代谢并发症。胰岛素抵抗的发展并不局限于 CKD，还发生在肥胖、2 型糖尿病和炎症性疾病中，人们很容易推测我的研究结果可能会扩展到其他疾病。幸运的是，我的导师博士的研究兴趣。加西亚和米奇至少部分与我的目标相似，而博士。 Chan、Justice 和 Taegtmeyer 可以帮助我解决实验问题。 我的初步结果表明，SIRP-α 表达增加是通过 NF-αB 发生的，而沉默肌肉细胞中的 SIRP-α 可以增强胰岛素信号传导并抑制蛋白质消耗。具体目标1：确定SIRP-α的酪氨酸磷酸化是否募集SHP2以及SIRP-α-SHP2复合物是否降低胰岛素受体和IRS-1的酪氨酸磷酸化。具体目标2：研究通过诱导CKD而全身敲除SIRP-α的小鼠。我的目标是研究在缺乏 SIRP-alpha 的情况下 CKD 如何影响胰岛素信号传导和肌肉代谢。我将确定 CKD 如何影响 SIRP-α 肌肉特异性 KO 小鼠的肌肉代谢。具体目标 3：我们还发现 CKD 小鼠心脏中 SIRP-α 表达增加。由于糖尿病会导致心脏纤维化并导致功能受损，因此我计划确定 SIRP-alpha KO 小鼠是否能够免受 CKD 刺激的心脏纤维化和功能下降的发展。 我的短期目标是实现这些具体目标，作为成为一名独立资助的首席研究员的前奏。我的长期目标是确定导致胰岛素信号传导受损和 CKD 并发症的机制。具体来说，我将提高教学课程和研讨会的知识和技能（例如细胞和分子生物学、资助和手稿写作、生物医学研究伦理和转化研究设计）。我相信我拥有成长为一名成功的研究者所必需的环境，包括强有力的指导、世界知名的职业咨询委员会以及参加当地和国家研究会议。为了扩展我的研究，我正在申请 VA-CDA，并希望开发治疗方法来改善患有 CKD、2 型糖尿病或肥胖等以胰岛素信号受损为特征的美国退伍军人的生活质量。