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: 8997114
• 负责人: Rajeev Malhotra
• 金额: $ 17.39万
• 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/8997114
• 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; Course Content; Data; Development; Disease; 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 Smooth Muscle; 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; mouse model; 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(由申请者提供)：本建议书描述了一项为期5年的心血管医学学术生涯发展培训计划。Malhotra博士(首席调查员)曾在哈佛大学接受过分子生物学和心血管疾病方面的培训，在哈佛大学担任本科生、研究生和医学生，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，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进行拟议中的研究。Kenneth Bloch博士作为导师的记录得到了证实，并培养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博士还将受益于共同导师Yu博士(BMP信号方面的专家)以及顾问Aikawa博士、Lee博士、Peterson博士和Dec.博士的专业知识。Malhotra博士将在Bloch博士的实验室附近拥有专门的办公室和研究空间，以设计和进行实验，并随时可以使用实施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)为培训内科科学家提供了理想的环境。作为CVRC的一名成员，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，将从哈佛医学院明确的课程和众多研讨会和教学课程中学习并成长为科学家和实验室负责人，并将能够使用麻省理工学院和哈佛医学院的广泛生物医学核心设施，以帮助成功完成他申请中概述的研究计划。Malhotra博士的研究计划侧重于血管钙化的机制，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，被认为是导致斑块不稳定的原因之一。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生有关。利用基质GLA蛋白缺乏诱导的小鼠血管钙化模型(MGP-/-小鼠)，突出了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，对BMP信号的药物抑制减少了MGP-/-小鼠血管钙化的负担，并提高了存活率。候选人建议用以下方式定义BMPs在血管钙化中的具体作用 两个目标：在目标1中，候选者的第一个目标是描述已知与成骨分化和血管钙化相关的下游信号通路(例如，Runx2、MSX2、Wnt和Notch信号)，这些信号通路受BMP信号调节。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模拟钙化来扩展他在体内的初步发现。对BMP信号的药物抑制提供了一种独特的策略来识别特定的下游信号通路，这些信号通路对于血管钙化是必不可少的，这些信号通路是由BMP调节的。Malhotra博士还将确定血管钙化在抑制BMP的情况下是否可逆，这将对血管疾病的机制和治疗具有重要意义。在目标2中，候选人将使用细胞培养和小鼠中的条件性基因敲除技术以及细胞培养中的小干扰核糖核酸技术来鉴定骨形态发生蛋白介导的血管钙化所必需的特定的骨形态发生蛋白I型受体(S)。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 心血管疾病的治疗。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制度环境相结合，Malhotra博士的目标是实现以下短期和长期的职业目标：(1)对导致血管钙化的基因表达计划有更广泛的了解。(2)确定BMP促进心血管钙化的分子机制，并在此过程中学习先进的分子生物学和条件性基因缺失的小鼠模型。(3)在他的导师、合作导师和咨询委员会的指导下，培养指导实验室、促进富有成效的研究合作、拨款撰写和成为独立的基础科学研究人员所需的技能。(4)在发奖后3-4年内成功申请R01拨款。(5)成为MGH CVRC的独立资助研究员，拥有领导心脏病学创新研究领域所需的专业知识，在该领域，分子生物学实验的结果最终将应用于人类疾病的研究。