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: 7472645
• 负责人: JOEL M HENDERSON
• 金额: $ 15.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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/7472645
• 关键词: Ablation; Actomyosin; American; Animal Model; Annual Reports; Area; Biological; Biomechanics; Biomedical Engineering; Biomedical Research; Biophysics; Blood Pressure; Cells; Contractile Proteins; Development; Development Plans; Elements; End stage renal failure; Functional disorder; Goals; Human; Hypertension; In Vitro; Injury; Investigation; Kidney; Kidney Diseases; Knowledge; Life; Maintenance; Measures; Mechanics; Methods; Molecular; Molecular and Cellular Biology; Myosin ATPase; Myosin Heavy Chains; Pathologic; Pathology; Physicians; Property; Protein Isoforms; Proteins; Public Health; RNA Interference; Renal function; Research; Research Personnel; Research Project Grants; Role; Societies; Standards of Weights and Measures; Structure; Surgical Models; Techniques; Theft; Time; Training Programs; Transgenic Organisms; Treatment Cost; Work; base; career; cost; glomerulosclerosis; improved; mouse model; novel strategies; podocyte; prevent; programs; research study; response; skills

DESCRIPTION (provided by applicant): 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 model to 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.

描述（由申请人提供）： 拟议培训计划的总体目标是通过在实验细胞和分子生物学领域以及理论和实验性细胞生物物理学领域中获得新知识和技能来增强申请人的病理和生物医学工程背景。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：制定一个积极的研究计划，研究机械现象在肾脏疾病中的作用。研究职业发展计划的主要目标将包括：1）在细胞和分子生物学技术应用于生物医学研究问题上的应用中获得全面知识和技能，以及2）在细胞“微生物力学”领域中发展专业知识，尤其是在测量活细胞生成的方法的理解和应用方面。拟议的研究项目将通过研究足细胞作为肾小球内的结构元素的作用来促进这些目标。该功能可能会在与肾小球高血压有关的病理状态下受到破坏，从而导致足细胞损伤和肾小球硬化。第一个目的是研究当使用药理和RNA干扰技术改变特定肌球蛋白蛋白亚型的功能时，足细胞的力产生特性如何改变。第二个目的是开发一种未能以调皮细胞特异性和时间控制的方式表达肌球蛋白重链MYH9的特定亚型的转基因小鼠模型。第三个目标将检查这种新小鼠模型对系统性高血压的病理生理反应。这些实验将有助于定义足细胞在维持肾小球结构中的结构和机械作用，并最终将有助于确定延迟进展到终结肾脏疾病的新方法：许多肾脏疾病常见的肾脏功能的永久丧失，这是许多肾脏疾病的常见，对社会的代价很高。末期肾脏疾病是对公共卫生的威胁，最终使美国公众每年超过220亿美元的治疗费用（USRDS 2003年度报告），并从其公民身上窃取了无数年的生产性人类生活。这项工作将是减少美国公众终结阶段肾脏疾病的损失的重要一步。