A systems approach to metabolic dysregulation in the heart

描述(由申请者提供)：项目概要/摘要本建议详细说明了一项为期五年的综合性培训计划，该计划旨在指导心血管医学领域的职业发展。申请人已经在布里格姆妇女医院完成了心血管医学的临床培训，并提出了一个专门设计的研究计划，以提供额外的基本培训，作为他向独立的医生-科学家职业生涯过渡的基础。通过概述的职业和科学计划，申请者的目标是利用他以前在心血管生理学和疾病方面的培训，以及在结构化和有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仪方面的技能，以期对心力衰竭发病机制下的代谢重塑有新的见解。博德研究所具有系统分析、基因组和代谢组学专长的国际知名科学家Vamsi Mootha博士和布里格姆妇女医院心肌细胞生物学和心肌生理学专家廖荣立博士已建立联合导师关系，以促进申请者的科学和职业发展。穆塔博士和廖博士的实验室将为申请者提供理想的环境，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，需要获得必要的培训。此外，穆塔博士和廖博士都有良好的导师记录，包括年轻的研究人员过渡到教员职位和独立实验室。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一系列生物学专业中增加补充科学专业知识，同时专注于申请人的职业发展。申请者的中心目标是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控因素。为此，申请人建议利用一种创新的基于高效液相色谱-质谱仪的平台，对心肌梗死后心力衰竭的小鼠模型进行全球心肌代谢评估和器官水平的流量分析。此外，利用基因组工具和系统分析，申请人最近已确定转录抑制物TGIF1可能是心脏代谢的调节因子，并将在体外确定TGIF1在调节体外培养的成人心肌细胞代谢基因表达、代谢功能和细胞收缩方面的作用。这两个互补而又独立的目标是将大规模发现科学与单基因假说驱动的研究结合起来。总的来说，从拟议的实验和结构性职业发展计划中获得的经验将作为申请者作为医生-科学家的独立学术生涯的基础。 公共卫生相关性：项目叙述尽管心血管疾病的诊断和治疗取得了进展，但心力衰竭患者的数量仍在以流行率上升。这项建议旨在确定在心力衰竭过程中心脏代谢发生的变化，以及这些有害变化背后的机制。通过这样做，我们希望找到治疗心力衰竭和心血管疾病的新方法。

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. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Despite advances in the diagnosis and treatment of cardiovascular disease, the number of patients with heart failure continues to rise at epidemic rates. This proposal aims to identify the changes that occur in heart metabolism during the course of heart failure and the mechanisms that underlie these deleterious changes. In doing so, we hope to identify new approaches to treat heart failure and cardiovascular disease.