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MECHANISMS OF PROTEIN ACCUMULATION IN RENAL HYPERTROPHY

肾肥大中蛋白质积累的机制

基本信息

批准号：
6489600
负责人：
HAROLD A FRANCH
金额：
$ 12.78万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-15 至 2003-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6489600
关键词：
calpain enzyme activity epidermal growth factor kidney hypertrophy laboratory rat lysosomes protein biosynthesis protein degradation tissue /cell culture transforming growth factors ubiquitin

项目摘要

The goal of this Career Development Award is to develop the skills to address the cellular mechanisms controlling hypertrophy in renal disease. The kidney responds to loss of nephrons or metabolic derangements by increasing the size of existing glomeruli and tubules rather than by duplicating nephrons. While this hypertrophy of the kidney helps the body adapt to conditions which require increased filtration and reabsorption, hypertrophy is not always beneficial. Diabetes mellitus and loss of renal mass cause renal hypertrophy that has been associated with the development of sclerosis and progressive loss of renal function. While the cellular mechanisms causing hypertrophy are unclear, recent advances in the control of cell growth provide an opportunity to address the mechanisms causing protein accumulation in hypertrophy. The candidate is an academic nephrologist with a longstanding interest in the cellular mechanisms of renal hypertrophy who is trying to develop an independent laboratory. The research development plan is aimed both to teach the candidate new techniques in control of cellular protein metabolism, and also broaden his back ground in mitogenic cell signaling, an area where he already has limited expertise. Experience with studying cellular mechanisms in vivo models of hypertrophy will be especially useful. The advisors and consultants have expertise in specific areas vital to both current and future research (Protein metabolism, mitogenic signaling, and hypertrophic renal diseases). The research plan addresses mechanisms of protein accumulation by renal epithelial cells. In tissue culture models of hypertrophy, it will investigate how EGF plus TGF beta decreases protein degradation Experiments examine the role that the metabolism of proteins that are targeted for lysosomal breakdown play in the increase in protein half- life. Results from this aim will define if a specific lysosomal import pathway acts to regulate protein accumulation in EGF+TGF beta and ammonium chloride mediated hypertrophy, and if specific candidate proteins are regulated. Using the mechanisms found in these in vitro experiments, studies will be performed in well defined rat models of renal hypertrophy. Results from this aim will determine if specific pathways of protein degradation play a role in the tissue specific protein accumulation seen in diabetic and acidotic models of renal hypertrophy, and test if our cell culture model accurately depicts the mechanisms associated with hypertrophy in vivo. It should also lay the ground work for further investigations into the mechanisms behind renal hypertrophy.

这个职业发展奖的目标是发展技能，解决控制肾脏肥大的细胞机制疾病肾脏对肾单位或代谢产物的损失作出反应，通过增加现有肾小球和肾小管的大小而引起的紊乱而不是复制肾单位。虽然这种肥大的肾脏帮助身体适应需要增加的条件过滤和重吸收，肥大并不总是有益的。糖尿病和肾脏质量损失导致肾脏肥大，与硬化症的发展和进行性肾功能丧失。虽然细胞机制导致肥大的原因尚不清楚，最近在控制细胞生长方面的进展提供了一个机会，以解决机制，在肥大中积累。候选人是一位学术肾病学家，研究肾脏肥大的细胞机制独立的实验室。该研究开发计划旨在教授候选人控制细胞蛋白质的新技术代谢，也拓宽了他在有丝分裂细胞的背景信号，这是一个他已经拥有有限专业知识的领域。经验通过研究肥大的体内模型中的细胞机制，特别有用。顾问和咨询人员具有以下方面的专业知识：对当前和未来研究至关重要的特定领域（蛋白质代谢、促有丝分裂信号传导和肥大性肾病）。该研究计划解决了肾脏蛋白质积累的机制，上皮细胞在肥大的组织培养模型中，研究EGF和TGF β如何减少蛋白质降解实验研究了蛋白质代谢的作用，靶向溶酶体分解在蛋白质半- 生活这一目标的结果将确定是否有特定的溶酶体输入途径起调节EGF+TGF β中蛋白质积累的作用，氯化铵介导的肥大，如果特定候选人蛋白质是有规律的。利用这些体外实验中发现的机制，实验中，研究将在明确定义的大鼠模型中进行，肾肥大这一目标的结果将决定是否特异性蛋白质降解途径在组织特异性在糖尿病和酸中毒模型中观察到的蛋白质积聚肥大，并测试我们的细胞培养模型是否准确地描述了与体内肥大相关的机制。它还应该奠定为进一步研究肾脏疾病背后的机制奠定基础肥厚