Actomyosin-Based Podocyte Contractility and Glomerular Pathobiology

基于肌动球蛋白的足细胞收缩性和肾小球病理学

• 批准号: 8245815
• 负责人: JOEL M HENDERSON
• 金额: $ 15.08万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245815
• 关键词: Ablation; Actomyosin; American; Animal Model; Annual Reports; Area; Atomic Force Microscopy; Biological; Biomechanics; Biomedical Engineering; Biomedical Research; Biophysics; Blood Pressure; Cell Line; Cells; Cellular biology; Contractile Proteins; Development; Development Plans; Elements; End stage renal failure; Exhibits; Functional disorder; Gene Expression; Generations; Genes; Goals; Human; Hypertension; In Vitro; Injury; Intervention; Investigation; Isometric Exercise; Kidney; Kidney Diseases; Knock-out; Knowledge; Life; Maintenance; Measures; Mechanics; Methods; Modeling; Molecular; Molecular Biology; Mus; Myosin ATPase; Myosin Heavy Chains; Nonmuscle Myosin Type IIA; Pathologic; Pathology; Phase; Physicians; Property; Protein Isoforms; Proteins; Public Health; RNA Interference; Renal function; Renal glomerular disease; Research; Research Personnel; Research Project Grants; Role; Societies; Structure; Surgical Models; System; Techniques; Testing; Theft; Time; Traction; Training Programs; Transgenic Mice; Transgenic Organisms; Treatment Cost; Work; base; body system; career; career development; cost; glomerular function; glomerulosclerosis; improved; knockout gene; mouse model; non-muscle myosin; novel strategies; podocyte; prevent; programs; research study; response; skills; standard measure; tool

The overall goal of the proposed training program is to enhance the applicant's background in pathology and biomedical engineering through acquisition of new knowledge and skill in the areas of experimental cell and molecular biology, and theoretical and experimental cellular biophysics. This new knowledge will help to facilitate the applicant's ultimate career objective as an academic physician: to develop an active research program investigating the role of mechanical phenomena in renal disease. Primary objectives of the research career development plan will include: 1) attainment of comprehensive knowledge and skill in the application of cell and molecular biological techniques to biomedical research questions, and 2) development of specialized knowledge in the area of cell "micro-biomechanics", particularly with respect to the understanding and application of methods used to measure mechanical forces generated by living cells. The proposed research project will facilitate these objectives through an investigation of the role of the podocyte as a structural element within the glomerulus. This function may be undermined in pathologic states associated with glomerular hypertension, resulting in podocyte injury and glomerulosclerosis. the first aim will be to investigate how the force-generating properties of podocytes change when the function of specific myosin protein subtypes is altered using pharmacologic and RNA interference techniques. The second aim will be to develop a transgenic mouse model that fails to express a specific isoform of myosin heavy chain, Myh9, in a podocyte-specific fashion and under temporal control. The third aim will examine the pathophysiologic response of this new mouse modefto systemic hypertension. These experiments will help define the structural and mechanical role of the podocyte in maintaining glomerular structure, and will ultimately help identify new approaches to delay progression to end stage renal disease: the permanent loss of kidney function that is common to many kidney diseases, and costly to society. End-stage renal disease is a menace to public health, ultimately costing the American public over $22 billion in treatment costs annually (USRDS 2003 Annual Report), and stealing untold years in productive human life from its citizens. This work will serve as an important step in the effort to reduce the toll of end stage renal disease on the American public.

拟议培训计划的总体目标是增强申请人病理学背景和 生物医学工程通过在实验细胞和 分子生物学以及理论和实验性细胞生物物理学。这些新知识将有助于 促进申请人作为学术医师的最终职业目标：进行积极的研究 研究机械现象在肾脏疾病中的作用的计划。主要目标 研究职业发展计划将包括：1）获得全面知识和技能 细胞和分子生物技术在生物医学研究问题上的应用，2） 细胞“微动力学”领域的专业知识，特别是关于 了解和应用用于测量活细胞产生的机械力的方法。这 拟议的研究项目将通过调查足细胞的作用来促进这些目标 作为肾小球内的结构元素。该功能可能会在病理状态下受到破坏 与肾小球高血压有关，导致足细胞损伤和肾小球硬化。第一个目标 将研究特异性功能时，将如何改变足细胞的力性能 使用药理和RNA干扰技术改变肌球蛋白蛋白亚型。第二个目标 将开发一种未表达肌球蛋白重链的特定亚型的转基因小鼠模型， MYH9，以特定于型细胞的方式和时间控制。第三个目标将检查 这种新的小鼠ModeFTO系统性高血压的病理生理反应。这些实验会有所帮助 定义足细胞在维持肾小球结构中的结构和机械作用，并将 最终有助于确定延迟进展到结束肾脏疾病的新方法：永久损失 许多肾脏疾病常见的肾功能，对社会而言是昂贵的。末期肾脏疾病 是对公共卫生的威胁，最终使美国公众超过220亿美元的治疗费用 每年（USRDS 2003年度报告），并从其公民身上窃取生产力的人类生活。 这项工作将是减少终阶段肾脏疾病的损失的重要一步 美国公众。