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: 8821393
• 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/8821393
• 关键词: Address; Advisory Committees; Affect; Age; American; Binding; Binding Proteins; Biomedical Research; Blood Pressure; Cardiac; Cardiac Myocytes; 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; Inflammation; Inflammatory; Information Systems; Inherited; Insulin; Insulin Receptor; Insulin Resistance; Intracellular Signaling Proteins; Justice; Kidney; Kidney Diseases; Knowledge; Lead; Manuscripts; Measures; Mediating; Mediator of activation protein; Membrane; Mentors; Mentorship; Molecular Biology; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Proteins; Mutant Strains Mice; Myoblasts; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Obesity; PTPN11 gene; PTPNS1 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; career; coronary fibrosis; cytokine; improved; in vivo; inhibitor/antagonist; 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）：