KLF4 as a Regulator of Endothelial Thrombotic Function

KLF4 作为内皮血栓功能的调节剂

• 批准号: 7186356
• 负责人: Anne Hamik
• 金额: $ 12.9万
• 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: 2007-04-05 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186356
• 关键词: Adhesives; Advisory Committees; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Injury; Biochemical; Biological Assay; Biology; Biomechanics; Blood; Blood Vessels; Blood coagulation; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Cycle Progression; Chromatin Structure; Clinical; Coagulants; Coagulation Process; Collaborations; Depth; Development; Dominant-Negative Mutation; Endothelial Cells; Endothelium; Enhancers; Environment; Exposure to; Family; Gelshift Analysis; Gene Chips; Gene Expression; Gene Targeting; Hospitals; Human; Immunoprecipitation; In Vitro; Infection; Inflammatory; Knowledge; Laboratories; Measures; Mediating; Medical; Medicine; Mentors; Modeling; Modification; Molecular; Molecular Biology; Mus; NF-kappa B; Nature; Physiological; Plasminogen Activator Inhibitor 1; Postdoctoral Fellow; Principal Investigator; Process; Program Development; Property; Protein Overexpression; Proteins; Rate; Regulation; Repression; Research; Resources; Scientist; Small Interfering RNA; Stimulus; Surface; Thrombomodulin; Thromboplastin; Thrombosis; Time; Tissues; Training; Training Programs; Transcriptional Regulation; Transducers; Transfection; Transgenic Animals; Transgenic Mice; Transgenic Model; Umbilical vein; Venous; Woman; Work; Zinc Fingers; abstracting; activated Protein C; base; career; cytokine; design; experience; exposed human population; fluidity; human NOS3 protein; in vivo; member; monolayer; novel strategies; p65; programs; promoter; protein expression; research study; shear stress; skills; transcription factor

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in cardiovascular medicine. The principal investigator has completed the clinical training in cardiovascular medicine at Brigham and Women's Hospital and will now embark upon a program which is particularly designed to expand her scientific experience such that she develops the skills required for an independent research career. This program will provide in-depth knowledge and experience in molecular biology, in particular transcriptional regulation, and in transgenic animal studies. Dr. Mukesh K. Jain will mentor the principal investigators scientific development. Dr. Jain has a very active laboratory and is the director of the Program in Cardiovascular Transcriptional Biology at Brigham and Women's Hospital. He has trained several post-doctoral fellows. The training will be enhanced by valuable experiences in the laboratories of three collaborators. Laminar flow/shear stress studies will be conducted in the laboratory of Dr. Elezar Edelman, Ex vivo coagulation studies will be performed with Dr. Viji Balasubramanian. In vivo thrombosis experiments on transgenic mice will be performed in the laboratory of Dr. William Fay. Vasoreactivity experiments will be done in collaboration with Dr. Thomas Michel. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice. The project is designed to determine the effect of the transcription factor KLF4 on endothelial thrombotic function. Preliminary work demonstrates that this factor is expressed in endothelial cells, is induced by laminar flow, and suggest that it is a potent regulator of factors which determine the anti-thrombotic nature of healthy endothelium. The proposed experiments will define the function and targets of endothelial KLF4. Studies will include a detailed analysis of coagulation protein expression and activity, ex vivo and in vivo coagulation studies with KLF4 overexpression (by adenoviral infection and transgenic models, respectively) and "knockdown" (by siRNA and a dominant negative construct). The molecular mechansims of KLF4's function as a transcriptional regulator will be studied in detail. The Cardiovascular Division at Brigham & Women's Hospital and the Longwood Medical Campus provide innumerable clinical and scientific resources- an ideal environment for training a clinician-scientist. (End of Abstract)

描述（由申请人提供）： 该提案描述了一个为期 5 年的心血管医学学术职业发展培训计划。主要研究者已完成心血管临床培训 布莱根妇女医院的医学博士，现在将开始一项特别是 旨在扩展她的科学经验，以便她发展独立研究职业所需的技能。该计划将提供分子生物学（特别是转录调控）和转基因动物研究方面的深入知识和经验。 Mukesh K. Jain 博士将指导主要研究人员的科学发展。 Jain 博士拥有一个非常活跃的实验室，并且是布莱根妇女医院心血管转录生物学项目的主任。培养了多名博士后。三位合作者实验室的宝贵经验将加强培训。层流/剪切应力研究将在 Elezar Edelman 博士的实验室进行，离体凝血研究将与 Viji Balasubramanian 博士一起进行。转基因小鼠体内血栓形成实验将在 William Fay 博士的实验室进行。血管反应性实验将与托马斯·米歇尔博士合作完成。此外，由备受推崇的医学科学家组成的咨询委员会将提供科学和职业建议。该项目旨在确定转录因子 KLF4 对内皮血栓功能的影响。初步工作表明，该因子在内皮细胞中表达，由层流诱导，并表明它是决定健康内皮抗血栓形成性质的因子的有效调节剂。拟议的实验将定义内皮 KLF4 的功能和靶点。研究将包括凝血蛋白表达和活性的详细分析、KLF4过表达（分别通过腺病毒感染和转基因模型）和“敲低”（通过siRNA和显性失活构建体）的离体和体内凝血研究。将详细研究KLF4作为转录调节因子的分子机制。布莱根妇女医院的心血管科和朗伍德医学园区提供了无数的临床和科学资源——为培训临床医生科学家提供了理想的环境。 （摘要完）