A systems approach to metabolic dysregulation in the heart

项目概述/摘要：本提案详细介绍了一个全面的五年培训计划，以指导学术心血管医学的职业发展。申请人在布里格姆妇女医院完成了心血管医学的临床培训，并提出了一个专门构建的研究项目，以提供额外的基本培训，这将作为他过渡到独立职业的基础，作为一名医生科学家。通过概述的职业和科学计划，申请人旨在利用他之前在心血管生理学和疾病方面的培训，以及在结构化和指导的科学环境中新获得的系统分析，基因组学，代谢组学和大分子质谱方面的技能，以便对心力衰竭发病机制的代谢重塑产生新的见解。为促进申请人的科学和职业发展，布罗德研究所国际知名的系统分析、基因组学和代谢组学专家Vamsi Mootha博士与布莱根妇女医院心肌细胞生物学和心肌生理学专家Ronglih Liao博士建立了联合指导。Mootha博士和Liao博士的实验室将为申请人提供理想的环境，拥有最先进的基础设施，分析技能，无数的资源和丰富的科学基础，以获得必要的培训。此外，Mootha博士和Liao博士都有良好的指导记录，包括年轻的研究人员过渡到教师职位和独立实验室。此外，一个由来自哈佛社区的杰出科学家和临床医生组成的专家学术咨询委员会将在生物专业领域增加互补的科学专业知识，同时专注于申请人的职业发展。申请人的中心目标是1)全面描述导致心力衰竭发病机制的基本代谢紊乱，以及2)确定这一有害过程的分子调节因子。为此，申请人提出利用创新的高效液相色谱-质谱平台对心肌进行整体代谢评估，并在心肌梗死后心力衰竭小鼠模型中进行器官水平的通量分析。此外，使用基因组工具和系统分析，申请人最近确定了转录抑制因子TGIF1作为心脏代谢的假定调节因子，并将确定TGIF1在体外分离成人心肌细胞中介导代谢基因表达、代谢功能和细胞收缩性的作用。这两个互补而又独立的目标有助于将大规模发现科学与单基因假设驱动的研究结合起来。综上所述，从实验中获得的经验和结构化的职业发展计划将作为申请人作为一名医师-科学家的独立学术生涯的基础。

DESCRIPTION (provided by applicant): PROJECT SUMMARY / ABSTRACT This proposal details a comprehensive five-year training program for mentored career develop in academic cardiovascular medicine. The applicant has completed clinical training in cardiovascular medicine at Brigham and Women's Hospital and proposes a research program specifically constructed to provide additional essential training that will serve as the foundation for his transition towards an independent career as a physician-scientist. Through the career and scientific plans outlined, the applicant aims to leverage his prior training in cardiovascular physiology and disease with newly acquired skills in systems analysis, genomics, metabolomics and macro-molecule mass spectrometry within a structured and mentored scientific environment, in order to shed novel insight into the metabolic remodeling that underlies the pathogenesis of heart failure. A joint mentorship between Dr. Vamsi Mootha, an internationally-recognized scientist at the Broad Institute with expertise in systems analysis, genomics and metabolomics, and Dr. Ronglih Liao, an expert in cardiomyocyte biology and myocardial physiology at Brigham and Women's Hospital, has been established to foster the applicant's scientific and career development. Dr. Mootha's and Dr. Liao's laboratories will provide an ideal environment for the applicant, with state-of-the-art infrastructure, analytical skills, innumerable resources and rich scientific base required to obtain the necessary training. Additionally, both Dr. Mootha and Dr. Liao have a proven track record of mentorship, including with young investigators transitioning to faculty positions and independent laboratories. Furthermore an expert academic advisory committee of distinguished scientists and clinicians from the Harvard community will add complementary scientific expertise in a spectrum of biological specialties, while focused on the career development of the applicant. The applicant's central goal is 1) to comprehensively characterize the fundamental metabolic derangements that contribute to the pathogenesis of heart failure as well as 2) to identify the molecular regulators of this deleterious process. Towards this, the applicant proposed to utilize an innovative HPLC-mass spectrometry based platform for global metabolic assessment of myocardium and as well as organ-level flux analysis in a mouse model of post-myocardial infarct heart failure. Also, using genomic tools and systems analysis, the applicant has recently identified the transcriptional repressor TGIF1 as a putative regulator of cardiac metabolism, and will determine the role of TGIF1 in mediating metabolic gene expression, metabolic function and cell contractility in isolated adult cardiomyocytes, in-vitro. These two complementary, yet independent, Aims serve to integrate both large scale discovery science with single gene hypothesis-driven investigation. Collectively, the experience gained from the proposed experiments and structural career development plan will serve as the foundation for the applicant's independent academic career as a physician-scientist.