The Role of Bone Morphogenetic Proteins in Vascular Calcification

描述（由申请人提供）：此提案描述了一个为期5年的心血管医学学术生涯发展培训计划。Malhotra博士（首席研究员）在哈佛大学本科、研究生和医学院学生时期接受过分子生物学和心血管疾病方面的培训，在马萨诸塞州总医院（MGH）担任内科住院医师和心血管研究员，在基础研究调查方面拥有多年的经验和生产力。Malhotra博士将在哈佛医学院医学和麻醉教授Kenneth Bloch博士的指导下在MGH进行拟议的研究，Kenneth Bloch博士作为导师有着良好的记录，并培养和支持了许多早期研究人员转变为独立资助的科学家。除了他的导师之外，Malhotra博士还将受益于共同导师Yu博士（BMP信号专家）和顾问Dr。Aikawa, Lee， Peterson和Dec. Malhotra博士将在Bloch博士的实验室附近有专门的办公室和研究空间，可以设计和执行实验，并且可以随时使用执行他的研究计划所需的设备和设施。此外，MGH心血管研究中心（CVRC）为培养医师科学家提供了理想的环境。作为CVRC的一员，Malhotra博士将从100多名教职员工和博士后研究员那里获得专业知识，将开展长期和富有成效的研究合作，将从哈佛医学院的明确课程课程和许多研讨会和教学课程中学习和成长为一名科学家和实验室负责人。并将获得MGH和哈佛医学院广泛的生物医学核心设施，以帮助他成功完成申请中概述的研究计划。Malhotra博士的研究重点是血管钙化的机制，与急性冠状动脉综合征、主动脉综合征和外周动脉疾病的发病机制高度相关。血管壁钙化是心血管事件的重要危险因素，被认为有助于斑块不稳定。骨形态发生蛋白（BMPs）在人类动脉粥样硬化病变中的表达与血管壁钙化的发展有关。利用基质Gla蛋白缺乏诱导的血管钙化小鼠模型（MGP-/-小鼠）强调了BMPs在血管钙化发病机制中的重要作用。在初步研究中，Malhotra博士观察到，BMP信号的药理抑制可以减轻MGP-/-小鼠血管钙化的负担，提高生存率。候选人建议用以下方法来定义bmp在血管钙化中的具体作用

DESCRIPTION (provided by applicant): 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.