The Molecular Mechanisms of KLF2 Regulation and Function in Endothelial Cells

KLF2在内皮细胞中调控和功能的分子机制

• 批准号: 7268319
• 负责人: G. Brandon B Atkins
• 金额: $ 13.47万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-06 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268319
• 关键词: Adhesives; Advisory Committees; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Area; Atherosclerosis; Base Pairing; Biochemical; Biology; Biomechanics; Blood; Blood Vessels; Boxing; Cardiology; Cardiovascular Diseases; Cardiovascular system; Clinical; Coagulants; Collaborations; Depth; Development; Development Plans; Disease; Endothelial Cells; Endothelium; Environment; Family; Gene Expression; General Hospitals; Genes; Goals; Health; Homeostasis; In Vitro; Inflammatory; Knowledge; Kruppel-like transcription factors; Laboratories; LacZ Genes; Mass Spectrum Analysis; Massachusetts; Mediating; Medical; Medicine; Mentors; Mentorship; Molecular; Mus; Nature; Numbers; Physiological; Principal Investigator; Program Development; Property; Protein Overexpression; Regulation; Research; Research Institute; Research Proposals; Resources; Role; Scientist; Small Interfering RNA; Stimulus; Stress; Structure; Surface; Thrombosis; Training; Training Programs; Transducers; Transgenic Mice; Vascular Endothelium; Work; Yeasts; Zinc Fingers; base; career; cytokine; design; experience; fluidity; human NOS3 protein; improved; in vivo; member; muscle enhancer factor-2A; novel; novel strategies; programs; promoter; research study; shear stress; symposium; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): This proposal describes a comprehensive five year training program for the development of the Principal Investigator's (PI) academic career in Cardiovascular Medicine. The PI has completed clinical training in Cardiology at Massachusetts General Hospital (MGH) and will now embark upon a rigorous training program that is tailored to provide the experience, mentorship, and resources required for an eventual independent research career. This program provides the PI with the experience to gain further in-depth knowledge and expertise in Molecular and Transcriptional Biology. Dr. Mukesh K. Jain, Director of the Case Cardiovascular Research Institute (CVRI), will mentor the PI's scientific development. As detailed in this proposal, the research environment is ideal and Dr. Jain has proven to be an exemplary mentor. The training will be enhanced by collaborations with the laboratories of Dr. John Schwarz, Dr. John Lowe, and Dr. Thomas Michel who will provide their respective expertise in the areas of in vivo study of MEF2 transcription factors, laminar flow/sheer stress and vasoreactivity experiments. In addition, an advisory committee of renowned medical scientists will provide scientific and career guidance. This highly structured career development plan also includes relevant coursework/symposia and conferences. The project is designed to elucidate the role of the transcription factor KLF2 in endothelial biology. Preliminary work shows that this factor is expressed in endothelial cells, is induced by laminar flow, and is a potent and novel transcriptional regulator of factors which determine the anti-thrombotic nature of healthy endothelium. Based of these observations, it is hypothesized that KLF2 is a key molecular switch involved in the regulation of endothelial function and vascular homeostasis in health and disease. The Specific Aims of this proposal are: 1) To determine the molecular basis of KLF2 regulation in vitro and in vivo. 2) To determine the mechanistic basis of KLF2's ability to induce eNOS gene expression. 3) To assess for effects of endothelial specific KLF2 overexpression on gene expression and vasoreactivity in vivo. Relevance: Atherosclerosis and cardiovascular disease is a major clinical problem affecting over 13 million people. The research proposed in this project aims to improve our understanding of the molecular mechanisms of cardiovascular disease with the ultimate goal of developing novel therapies for treatment.

描述（由申请人提供）：该提案描述了一项全面的五年培训计划，以开发主要研究者（PI）心血管医学学术生涯。 PI已在马萨诸塞州综合医院（MGH）完成心脏病学临床培训，现在将启动一项严格的培训计划，该计划旨在提供最终独立研究职业所需的经验，指导和资源。该计划为PI提供了经验，以进一步获得分子和转录生物学方面的深入知识和专业知识。病例心血管研究所（CVRI）主任Mukesh K. Jain博士将指导PI的科学发展。正如该提案中详细介绍的那样，研究环境是理想的，Jain博士已被证明是典范的导师。与John Schwarz博士，John Lowe博士和Thomas Michel博士的实验室的合作将得到增强培训，他们将在体内研究MEF2转录因素，层流量/纯粹的压力和血管反应性实验方面提供各自的专业知识。此外，著名的医学科学家咨询委员会将提供科学和职业指导。这个高度结构化的职业发展计划还包括相关的课程/研讨会和会议。该项目旨在阐明转录因子KLF2在内皮生物学中的作用。初步工作表明，该因子在内皮细胞中表达，由层流诱导，是一个有效且新颖的转录调节因子，这些因素决定了健康内皮的抗栓性性质。基于这些观察结果，假设KLF2是健康和疾病中内皮功能和血管稳态调节的关键分子转换。该提案的具体目的是：1）确定体外和体内KLF2调节的分子基础。 2）确定KLF2诱导eNOS基因表达能力的机理基础。 3）评估内皮特异性KLF2过表达对体内基因表达和血管反应性的影响。相关性：动脉粥样硬化和心血管疾病是影响超过1300万人的主要临床问题。该项目中提出的研究旨在提高我们对心血管疾病的分子机制的理解，其最终目的是开发新的治疗疗法。