Chronic_Kidney_Disease_and_Impaired_Actions_of_Insulin

描述(由申请人提供)： Fliser等人。他发现，患有IgA或遗传性肾病的非糖尿病患者存在胰岛素抵抗，血清肌酐和肾小球滤过率接近正常，指出这种并发症并不局限于透析患者。他们得出结论，导致胰岛素抵抗的是慢性肾脏疾病(CKD)，而不是一种特定的肾脏疾病。然而，导致慢性肾脏病胰岛素抵抗的机制尚不清楚：胰岛素似乎与其受体正常结合，但细胞内信号转导存在缺陷。我的项目I基于我发现的一个新的途径，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质-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如何导致骨骼肌萎缩和心肌纤维化和功能障碍。慢性肾脏病是美国退伍军人的主要担忧，因为它总是会导致发病率和死亡率的增加，包括胰岛素抵抗。我的长期目标是确定导致慢性肾脏病胰岛素抵抗的机制，并开发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慢性肾脏病，而是发生在肥胖、2型糖尿病和炎症条件下，人们很容易推测我的研究结果可能会延伸到其他条件下。幸运的是，我的导师加西亚博士和米奇博士的研究兴趣至少在一定程度上与我的目标相似，而陈博士、正义与泰格迈尔博士可以帮助我解决实验问题。我的初步结果表明，SIRP-α的表达增加是通过核因子-α，沉默肌肉细胞中的SIRP-α增强了胰岛素信号并抑制了蛋白质的消耗。具体目的1：确定SIRP-α的酪氨酸磷酸化是否招募SHP2，以及SIRP-α-SHP2复合体是否减少胰岛素受体和IRS-1的酪氨酸磷酸化。特异性目的2：通过诱导CKD，研究SIRP-α全身KO小鼠。我的目标是研究在缺乏SIRP-α的情况下CKD如何影响胰岛素信号和肌肉代谢。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的表达增加。由于糖尿病可以导致心脏纤维化和功能受损，我计划确定SIRP-αKO小鼠是否能够防止CKD刺激的心脏纤维化和功能下降的发展。我的短期目标是解决这些具体目标，作为成为一名独立资助的原则调查员的前奏。我的长期目标是确定导致胰岛素信号转导受损和慢性肾脏病并发症的机制。具体地说，我将在教学课程和研讨会(例如细胞和分子生物学、补助金和手稿写作、生物医学研究中的伦理和翻译研究设计)中加强我的知识和技能。我相信我有成长为一名成功的调查员所需的环境，包括强大的导师，世界知名的职业咨询委员会，以及参加地方和国家研究会议。为了扩大我的研究范围，我正在申请VA-CDA，并希望开发治疗方法来提高美国退伍军人的生活质量，这些退伍军人患有慢性肾脏病、2型糖尿病或肥胖等以胰岛素信号受损为特征的疾病。

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.