MECHANISMS OF PROTEIN ACCUMULATION IN RENAL HYPERTROPHY

肾肥大中蛋白质积累的机制

• 批准号: 6137931
• 负责人: HAROLD A FRANCH
• 金额: $ 12.18万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137931
• 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

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.

该职业发展奖的目标是培养以下技能： 解决控制肾肥大的细胞机制 疾病。 肾脏对肾单位损失或代谢做出反应 通过增加现有肾小球和肾小管的大小而造成紊乱 而不是通过复制肾单位。 虽然这种肥大 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。 糖尿病和肾质量损失导致肾肥大 与硬化和进行性的发展有关 肾功能丧失。虽然细胞机制导致 肥大尚不清楚，细胞生长控制的最新进展 提供了一个机会来解决导致蛋白质的机制 堆积肥大。 候选人是一位有着长期兴趣的学术肾病专家 在肾肥大的细胞机制方面谁正在努力开发 一个独立的实验室。 研究开发计划的目标是 教授候选人控制细胞蛋白质的新技术 新陈代谢，并拓宽了他在有丝分裂细胞方面的背景 信号传输，他在这个领域的专业知识已经有限。 经验 通过研究体内肥大模型的细胞机制 特别有用。 顾问和顾问拥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、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，它将 研究 EGF 加 TGF beta 如何减少蛋白质降解 实验检验了蛋白质代谢的作用 针对溶酶体分解在蛋白质半数增加中发挥作用 生活。 该目标的结果将确定特定的溶酶体进口是否 途径作用于调节EGF+TGFβ中的蛋白质积累和 氯化铵介导的肥大，如果有特定候选者 蛋白质受到调节。利用这些体外发现的机制 实验、研究将在明确的大鼠模型中进行 肾肥大。 这一目标的结果将决定是否具体 蛋白质降解途径在组织特异性中发挥作用 糖尿病和酸中毒肾模型中观察到的蛋白质积累 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。 还应奠定 为进一步研究肾脏背后的机制奠定基础 肥大。