The Role of Bone Morphogenetic Proteins in Vascular Calcification

骨形态发生蛋白在血管钙化中的作用

• 批准号: 8635607
• 负责人: Rajeev Malhotra
• 金额: $ 13.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635607
• 关键词: Advisory Committees; Alkaline Phosphatase; Anesthesia procedures; Animals; Aorta; Area; Arterial Fatty Streak; Arteries; Award; Basic Science; Binding; Biology; Biomedical Research; Blood Vessels; Bone Morphogenetic Proteins; Calcified; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Clinical; Collaborations; Core Facility; Data; Development; Disease; Educational Curriculum; Environment; Equipment; Evaluation; Event; Exhibits; Faculty; Fostering; Foundations; Functional disorder; Funding; Gene Deletion; Gene Expression; General Hospitals; Genes; Goals; Grant; Growth; Health; Heart Valve Diseases; Human; In Vitro; Internal Medicine; Investigation; Knowledge; Laboratories; Laboratory Scientists; Lead; Learning; Ligands; Low Density Lipoprotein Receptor; Massachusetts; Medial; Mediating; Mediator of activation protein; Medical Students; Medicine; Mentors; Mesenchymal; Modeling; Molecular; Molecular Biology; Mus; Myocardial Infarction; Osteocalcin; Osteogenesis; Pathogenesis; Pathway interactions; Peripheral arterial disease; Pharmaceutical Preparations; Phenotype; Physicians; Play; Postdoctoral Fellow; Prevention; Principal Investigator; Productivity; Program Development; Protein Deficiency; Protein Inhibition; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Syndrome; TNFSF11 gene; Techniques; Training; Training Programs; Tumor necrosis factor receptor 11b; Universities; Vascular Diseases; Vascular calcification; Writing; acute coronary syndrome; base; bone morphogenetic protein 2; bone morphogenetic protein receptor type I; calcification; cardiovascular risk factor; career; design; effective therapy; experience; graduate student; human disease; improved; in vivo; inhibitor/antagonist; innovation; insight; knockout gene; matrix Gla protein; medical schools; member; notch protein; novel; osteogenic; osteopontin; prevent; professor; progenitor; programs; receptor; research study; skills; success; therapeutic target; undergraduate student

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.

描述（由申请人提供）：本提案描述了心血管医学学术生涯发展的5年培训计划。Malhotra博士（主要研究者）曾在哈佛大学担任本科生、研究生和医科学生，并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，接受过分子生物学和心血管疾病方面的培训，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学教授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，并促进和支持了许多早期研究人员向独立资助的科学家的转变。除了他的导师，Malhotra博士将受益于共同导师Yu博士（BMP信号专家）和顾问Aikawa博士，Lee博士，Peterson博士和Dec博士的专业知识Malhotra博士将在Bloch博士实验室附近拥有专门的办公室和研究空间，以设计和执行实验，并将随时获得进行研究计划所需的设备和设施。此外，MGH心血管研究中心（CVRC）为培训医生科学家提供了理想的环境。Malhotra博士将从100多名教师和博士后研究员的专业知识中获益，将发展长期和富有成效的研究合作，将从哈佛医学院定义的课程中学习和成长为科学家和实验室领导者，以及许多研讨会和教学会议，并将有机会获得广泛的生物医学核心设施在MGH和哈佛医学院，以帮助在他的申请中概述的研究计划的成功完成。Malhotra博士的研究项目主要集中在血管钙化的机制，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，并被认为有助于斑块不稳定。人动脉粥样硬化病变中骨形态发生蛋白（BMPs）的表达与血管壁钙化的发展相关。使用由基质Gla蛋白缺乏诱导的血管钙化的小鼠模型（MGP-/-小鼠）已经突出了BMP在血管钙化的发病机制中的重要作用。在初步研究中，Malhotra博士观察到BMP信号的药理学抑制降低了MGP-/-小鼠的血管钙化负担并提高了存活率。候选人建议通过以下内容定义BMP在血管钙化中的具体作用 两个目标：在目标1中，候选人的第一个目标是表征已知与成骨分化和血管钙化相关的下游信号通路（例如，Runx 2、Msx 2、Wnt和Notch信号传导）。Malhotra博士将通过使用培养的MGP-/-主动脉平滑肌细胞和主动脉外植体建立钙化模型来扩展他的初步体内研究结果。BMP信号的药理学抑制提供了一种独特的策略，以确定特定的下游信号通路，血管钙化所必需的BMP调制。Malhotra博士还将确定BMP抑制剂是否可以逆转血管钙化，这将对血管疾病的机制和治疗产生重要影响。在目标2中，候选人将在细胞培养和小鼠中使用条件基因敲除技术以及在细胞培养中使用小干扰RNA技术来鉴定BMP介导的血管钙化所必需的特异性BMP I型受体。加强对BMP介导的血管钙化机制的认识可能具有重要的临床意义，并为血管钙化的治疗提供新的见解和靶点。 心血管疾病的治疗。Malhotra博士将他在生物医学研究方面的培训和经验与成功的导师和支持性的机构环境相结合，旨在实现以下近期和长期的职业目标：（1）对导致血管钙化的基因表达程序有更广泛的理解。(2)确定骨形成蛋白促进心血管钙化的分子机制，并在此过程中学习分子生物学和小鼠模型中条件性基因缺失的先进技术。(3)在他的导师，共同导师和咨询委员会的指导下发展指导实验室，促进富有成效的研究合作，资助写作和成为独立的基础科学调查员的必要技能。(4)在获奖后3-4年内成功申请R 01资助。(5)成为MGH CVRC独立资助的研究员，拥有领导心脏病学创新研究领域所需的专业知识，其中分子生物学实验的发现最终应用于人类疾病的研究。