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

基本信息

批准号：
8794460
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
项目类别：
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/8794460
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

项目摘要

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）：该提案描述了一项为期5年的培训计划，以开发心血管医学的学术生涯。 Malhotra博士（首席研究员）曾在哈佛大学的本科生，研究生和医学生，并在马萨诸塞州综合医院（MGH）接受了内科居民和心血管研究员，并在基础研究调查中具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，他作为导师有着良好的记录，并支持了许多早期研究人员向独立资助的科学家的过渡和支持。除了他的导师外，Malhotra博士还将受益于Yu博士（BMP信号专家）和顾问Drs的专业知识。 Aikawa，Lee，Peterson和Dec。Malhotra博士将拥有专门的办公室和研究空间，以靠近Bloch博士的实验室设计和执行实验，并准备好访问执行其研究计划所需的设备和设施。此外，MGH心血管研究中心（CVRC）为培训医师科学家提供了理想的环境。作为CVRC的成员，Malhotra博士将从100多名教职员工和博士后研究员的专业知识中获利，将发展持久和富有成效的研究合作，作为科学家和实验室的领导者，从哈佛大学的医学院以及在许多研讨会上，在许多研讨会上，都可以访问和dictactic sess的科学家和实验室的领导者，并可以访问Mygh的范围，并将其访问范围。在成功完成其应用程序中概述的研究计划中。 Malhotra博士的研究计划着重于血管钙化的机制，与急性冠状动脉综合征，主动脉综合征和周围动脉疾病高度相关。血管壁的钙化是心血管事件的重要危险因素，被认为会导致牙菌斑不稳定。人动脉粥样硬化病变中骨形态发生蛋白（BMP）的表达与血管壁钙化的发展有关。通过基质GLA蛋白缺乏症（MGP - / - 小鼠）诱导的血管钙化的鼠模型的使用突显了BMP在血管钙化发病机理中的重要作用。在初步研究中，Malhotra博士观察到，BMP信号的药理抑制会减轻MGP - / - 小鼠中血管钙化的负担，并改善了存活率。候选人建议定义BMP在血管钙化中的特定作用两个目的：在AIM 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Runx2，MSX2，Wnt和Notch信号传导），这些途径受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对钙化进行建模来扩展其初步体内发现。 BMP信号的药理抑制提供了一种独特的策略，可以识别BMP调节的血管钙化必不可少的特定下游信号通路。 Malhotra博士还将确定血管钙化是否可以通过BMP抑制作用可逆，这将对血管疾病的机制和治疗具有重要意义。在AIM 2中，候选者将使用条件基因敲除技术，在细胞培养和小鼠中，以及小型干扰RNA技术在细胞培养中，使用条件基因敲除技术来确定BMP I型受体的特定BMP I受体。增强对血管钙化负责的BMP介导的机制的知识可能具有重要的临床意义，并为该机制提供了新的见解和目标心血管疾病的治疗。 Malhotra博士将他在生物医学研究方面的培训和经验结合在一起，与成功的机构环境相结合，旨在实现以下直接和长期的职业目标：（1）对基因表达计划进行更广泛的了解，从而实现血管钙化。（2）确定BMP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条件基因缺失的先进技术。（3）在其导师，联合学委员会和咨询委员会的指导下发展指导实验室，促进生产研究合作，授予写作以及成为独立的基础科学研究者的必要技能。（4）在其奖励启动后的3 - 4年内成功申请R01资金。（5）成为MGH CVRC的一名独立资助的研究者，并具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结果最终应用于人类疾病的研究。