This proposal describes a 5 year training program for the development of an academic career in Cardiovascular Medicine. Dr. Malhotra (Principal Investigator) has had training in molecular biology and cardiovascular disease as an undergraduate, graduate, and medical student at Harvard University and an internal medicine resident and cardiovascular fellow at Massachusetts General Hospital (MGH) and has years of experience and productivity in basic research investigation. Dr. Malhotra will conduct the proposed research at MGH with the guidance of Dr. Kenneth Bloch, Professor of Medicine and Anesthesia at Harvard Medical School, who has a proven track record as a mentor and has fostered and supported the transition of numerous early investigators into independently-funded scientists. In addition to his mentor, Dr. Malhotra will benefit from the expertise of co-mentor Dr Yu (an expert in BMP signaling) and advisors Drs. Aikawa, Lee, Peterson, and Dec. Dr. Malhotra will have dedicated office and research space in proximity to Dr. Bloch's laboratory to design and perform experiments and will have ready access to the equipment and facilities needed to carry out his research program. Furthermore, the MGH Cardiovascular Research Center (CVRC) provides an ideal environment for training physician-scientists. As a member of the CVRC, Dr. Malhotra will gain from the expertise of over 100 faculty and post-doctoral fellows, will develop long-lasting and productive research collaborations, will learn and grow as a scientist and laboratory leader from a defined course curriculum at Harvard Medical School and the many seminars and didactic sessions available, and will have access to a wide range of biomedical core facilities at MGH and Harvard Medical School to aid in the successful completion of the research program outlined in his application. Dr. Malhotra's research program focuses on the mechanisms of vascular calcification, highly relevant to the pathogenesis of acute coronary syndromes, aortic syndromes, and peripheral arterial disease. Calcification of the vessel wall is an important risk factor for cardiovascular events and is thought to contribute to plaque destabilization. The expression of bone morphogenetic proteins (BMPs) in human atherosclerotic lesions is associated with the development of vessel wall calcification. The use of a murine model of vascular calcification induced by matrix Gla protein deficiency (MGP-/- mice) has highlighted an essential role for BMPs in the pathogenesis of vessel calcification. In preliminary studies, Dr. Malhotra has observed that pharmacologic inhibition of BMP signaling reduces the burden of vascular calcification in MGP-/- mice and improves survival. The candidate proposes to define the specific role of BMPs in vascular calcification with the following two aims:
In Aim 1, the candidate's first objective is to characterize the downstream signaling pathways known to be associated with osteogenic differentiation and vascular calcification (e.g., Runx2, Msx2, Wnt and Notch signaling) that are modulated by BMP signaling. Dr. Malhotra will extend his preliminary in vivo findings by modeling calcification using cultured MGP-/- aortic smooth muscle cells and aortic explants. Pharmacologic inhibition of BMP signaling offers a unique strategy to identify specific downstream signaling pathways essential for vascular calcification that are modulated by BMPs. Dr. Malhotra will also ascertain whether vascular calcification is reversible with BMP inhibition, which would have important implications in the mechanisms and treatment of vascular disease.
In Aim 2, the candidate will identify the specific BMP type I receptor(s) essential for BMP-mediated vascular calcification using conditional gene knockout techniques, both in cell culture and in mice, and small interfering RNA techniques in cell culture. Enhancing knowledge of the BMP-mediated mechanisms responsible for vascular calcification may hold important clinical implications and provide new insights and targets for the treatment of cardiovascular disease. Combining his training and experience in biomedical research with a successful mentor and a supportive institutional environment, Dr. Malhotra aims to accomplish the following immediate and long-term career goals: (1) To develop a broader understanding of the gene expression program resulting in vascular calcification. (2) To determine the molecular mechanisms by which BMPs promote cardiovascular calcification and, in doing so, to learn advanced techniques in molecular biology and conditional gene deletion in murine models. (3) To develop under the guidance of his mentor, co-mentor, and advisory committee the necessary skills of directing a laboratory, fostering productive research collaborations, grant writing, and of becoming an independent basic science investigator. (4) To successfully apply for R01 funding within 3-4 years of his award initiation. (5) To become an independently-funded investigator at the MGH CVRC, with the expertise needed to lead an innovative research area in cardiology, in which the findings of experiments in molecular biology are ultimately applied to studies of human disease.
The discovery of new and effective treatments for cardiovascular diseases requires the identification of novel disease mechanisms. This proposal aims to enhance our mechanistic insights of vascular disease by focusing on a novel signaling pathway that contributes to the development of calcified arteries in humans. Success in identifying the specific molecules in this pathway implicated in the development of calcification will provide new targets for the prevention and treatment of heart attacks and peripheral arterial disease.
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