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）： Fliser et al.确定了患有伊加或遗传性肾病的非糖尿病患者存在胰岛素抵抗，血清肌酐和GFR值接近正常，指出这种并发症不仅限于透析患者。他们得出结论，慢性肾脏疾病（CKD）而不是特定的肾脏疾病导致胰岛素抵抗。然而，导致CKD胰岛素抵抗的机制尚未确定：胰岛素与其受体的正常结合似乎存在细胞内信号传导的缺陷。我的项目基于我发现的一种新途径，即CKD刺激膜结合的酪氨酸磷酸酶信号调节蛋白α（SIRP-α）的表达，导致胰岛素受体及其下游介体胰岛素受体底物-1的酪氨酸磷酸化减少。我的目标是确定CKD刺激的SIRP-α如何诱导骨骼肌萎缩和心肌纤维化和功能障碍。 CKD是美国退伍军人的主要关注点，因为它总是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，并制定治疗策略以预防其分解代谢并发症。胰岛素抵抗的发展不仅限于CKD，还发生在肥胖症、2型糖尿病和炎症性疾病中，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Garcia博士和Mitch博士的研究兴趣至少在一定程度上与我的目标相似，而Chan博士、Justice博士和Taegtmeyer博士可以帮助我解决实验问题。 我的初步结果表明，增加SIRP-α表达发生通过NF-α B和沉默SIRP-α在肌肉细胞中增强胰岛素信号传导和抑制蛋白质消耗。具体目标1：以确定SIRP-α的酪氨酸磷酸化是否募集SHP 2以及SIRP-α-SHP 2复合物是否降低胰岛素受体和IRS-1的酪氨酸磷酸化。具体目的2：通过诱导CKD研究SIRP-α的全身KO小鼠。我的目标是研究在SIRP-α缺失的情况下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。由于糖尿病可导致心脏纤维化和功能受损，因此我计划确定SIRP-α KO小鼠是否能防止CKD刺激的心脏纤维化和功能下降。 我的短期目标是解决这些具体目标作为前奏，成为一个独立资助的主要研究者。我的长期目标是确定导致胰岛素信号受损和CKD并发症的机制。具体来说，我将提高我的知识和技能，在教学课程加上研讨会（例如细胞和分子生物学，赠款和手稿写作，在生物医学研究和转化研究设计的伦理）。我相信我有必要的环境成长为一个成功的调查员，包括强大的导师，世界知名的职业咨询委员会和参与当地和国家的研究会议。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美国退伍军人的生活质量，这些退伍军人患有CKD，2型糖尿病或肥胖等疾病，其特征是胰岛素信号受损。