A systems approach to metabolic dysregulation in the heart

描述（由申请人提供）：项目概要/摘要本提案详细介绍了一个全面的五年培训计划，在学术心血管医学的指导职业发展。申请人已在布里格姆妇女医院完成了心血管医学的临床培训，并提出了一项专门为提供额外的基本培训而构建的研究计划，该计划将作为他向独立职业过渡的基础，作为医生科学家。通过概述的职业生涯和科学计划，申请人的目标是利用他在心血管生理学和疾病方面的先前培训，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分析技能，以摆脱对心力衰竭发病机制的代谢重塑的新见解。Broad研究所的国际知名科学家Vamsi Mootha博士在系统分析，基因组学和代谢组学方面具有专业知识，与Brigham and Women's Hospital的心肌细胞生物学和心肌生理学专家Ronglih Liao博士之间的联合指导已经建立，以促进申请人的科学和职业发展。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，一个由哈佛社区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专业领域提供补充科学专业知识，同时专注于申请人的职业发展。申请人的中心目标是1）全面表征导致心力衰竭发病机制的基本代谢紊乱，以及2）鉴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基于HPLC-质谱的平台，在心肌梗死后心力衰竭的小鼠模型中进行心肌的整体代谢评估以及器官水平通量分析。此外，使用基因组工具和系统分析，申请人最近鉴定了转录抑制因子TGIF 1作为心脏代谢的推定调节因子，并将在体外确定TGIF 1在介导分离的成年心肌细胞中的代谢基因表达、代谢功能和细胞收缩性中的作用。这两个互补但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相结合。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人作为医生科学家的独立学术生涯的基础。 公共卫生相关性：尽管在心血管疾病的诊断和治疗方面取得了进展，但心力衰竭患者的数量仍以流行率持续上升。该提案旨在确定心力衰竭过程中心脏代谢发生的变化以及这些有害变化的机制。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.