KLF4 as a Regulator of Endothelial Thrombotic Function

描述(由申请人提供)： 这份提案描述了一项为期5年的心血管医学学术生涯发展培训计划。首席研究员已完成心血管方面的临床培训 在布里格姆妇女医院的医学，现在将开始一个项目，特别是 旨在扩大她的科学经验，使她发展独立研究事业所需的技能。本课程将提供分子生物学，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。穆凯什·K·贾恩博士将指导主要研究人员的科学发展。Jain博士有一个非常活跃的实验室，是布里格姆妇女医院心血管转录生物学项目的主任。他培养了几名博士后研究员。将通过三个合作者的实验室的宝贵经验来加强培训。层流/剪应力研究将在Elezar Edelman博士的实验室进行，体外凝血研究将与Viji Balasubramanian博士一起进行。转基因小鼠的体内血栓实验将在威廉·费伊博士的实验室进行。血管反应性实验将与托马斯·米歇尔博士合作完成。此外，一个由备受尊敬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对内皮血栓形成功能的影响。初步工作表明，该因子在内皮细胞中表达，由层流诱导，提示它是决定健康内皮细胞抗血栓性质的因子的有效调节因子。拟议的实验将确定内皮细胞KLF4的功能和靶点。研究将包括对凝血蛋白表达和活性的详细分析，体外和体内凝血研究，KLF4过表达(分别通过腺病毒感染和转基因模型)和“敲除”(通过siRNA和显性负结构)。KLF4的S作为转录调控因子的分子机制将被详细研究。布里格姆妇女医院的心血管科和朗伍德医学院提供了无数的临床和科学资源--这是培养临床医生和科学家的理想环境。 (摘要结束)

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)