KLF4 as a Regulator of Endothelial Thrombotic Function

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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)