Multiplexed Imaging of Energy Metabolism in Murine Models of Heart Failure

描述(由申请者提供)：这份建议书描述了Marcello Panagia博士的五年职业发展和培训计划，他是一名内科科学家，在获奖时将在马萨诸塞州综合医院(MGH)完成心血管医学和高级心脏成像(MR/CT/PET)培训。在David Sosnovik博士和Robert Gerszten博士的指导下，Panagia博士现在正在着手一项尖端研究计划，该计划将他在心脏能量代谢方面的背景与先进的成像技术相结合。他的职业发展计划利用了MGH提供的广泛资源，汇集了一支强大的研究团队，他们拥有分子成像、代谢组学、信号转导和磁共振成像方面的专业知识。在资助期间，Panagia博士将在MGH的心内科和放射科担任教职，并在哈佛医学院担任教职。他的最终目标是成为一名独立的研究人员，利用先进的成像技术工具包研究能量代谢。获得这一奖项将使Panagia博士获得更多关于 他在光学成像、磁共振成像和光谱学、新陈代谢组学、生物统计学、研究设计和伦理学方面取得了巨大成功，并将促进他向研究独立性的过渡。除了提供进一步培训的机制外，该奖项还将允许帕纳吉亚博士继续研究心力衰竭中能量代谢的失调。心力衰竭是美国发病率和死亡率的主要原因，能量代谢失调是其发病机制的一个基本特征。然而，充分研究能量代谢过程的能力可以显著提高。尽管有价值，但目前的技术受到其复杂性、相对较低的吞吐量以及无法同时镜像多个进程的限制。Panagia博士假设，一种新的光学方法可以同时成像心脏和外周组织中的多条代谢和能量通路，并为心力衰竭的发病机制提供重要的见解。帕纳吉亚博士获得的初步结果表明，在心力衰竭的冠脉结扎模型中，这种方法是可行的。他已经证明，在这个模型中，使用18F-氟脱氧葡萄糖的切伦科夫发光明显区分了存活心肌和SCAR，并且线粒体靶向探针的同时成像提供了宝贵的时间和空间相干信息。这种光学方法将通过使用代谢活动的非侵入性测量来加强，例如通过磁共振成像的外周组织耗氧量，以及对血液和组织代谢物的高通量筛选(代谢组学)。帕纳吉亚博士建议将这项研究扩大到包括多种不同病因的心力衰竭模型，并更详细地研究 从代偿性心力衰竭过渡到失代偿性心力衰竭的能量特征。总而言之，通过在明确的研究计划和导师结构的背景下汇集尖端技术和全面的专家团队，Panagia博士将能够协同合并先进成像和能量代谢领域，以阐明心脏病理生理学基础的新机制，并阐述他成为独立研究人员所必需的技能。

DESCRIPTION (provided by applicant): This proposal describes a five-year career development and training plan for Dr. Marcello Panagia, a physician-scientist, who at the time of the award will have completed training in Cardiovascular Medicine and Advanced Cardiac Imaging (MR/CT/PET) at Massachusetts General Hospital (MGH). Under the mentorship of Dr. David Sosnovik and Dr. Robert Gerszten, Dr. Panagia is now embarking on a cutting-edge research plan that combines his background in cardiac energy metabolism with advanced imaging technologies. His career development plan, that leverages the extensive resources offered by MGH, brings together a robust team of investigators with expertise in molecular imaging, metabolomics, signal transduction and magnetic resonance imaging. During the period of funding, Dr. Panagia will have faculty positions in the Cardiology and Radiology Divisions at MGH as well as a faculty appointment at Harvard Medical School. His ultimate goal is to become an independent investigator studying energy metabolism with a sophisticated tool-kit of imaging technologies. Receipt of this award will allow Dr. Panagia to obtain additional training in optical imaging, magnetic resonance imaging and spectroscopy, metabolomics, biostatistics, research design and ethics, and will facilitate his transition to research independence. In addition to providing a mechanism for further training, the award will allow Dr. Panagia to continue studies in the dysregulation of energy metabolism in heart failure. Heart failure is a leading cause of morbidity and mortality in the United States and the dysregulation of energy metabolism is a fundamental feature of its pathogenesis. However, the capacity to adequately study the processes involved in energy metabolism could be significantly improved. Although valuable, current techniques are limited by their complexity, relatively low throughput, and inability to image multiple processes at the same time. Dr. Panagia hypothesizes that a novel optical approach can permit the simultaneous imaging of multiple metabolic and energetic pathways in the heart and peripheral tissues and provide important insights into heart failure pathogenesis. Dr. Panagia has obtained preliminary results that show the feasibility of this approach in a coronary ligation model of heart failure. He has shown that Cerenkov luminescence using 18F- fluorodeoxyglucose in this model clearly differentiates viable myocardium from scar and that simultaneous imaging with mitochondrial-targeted probes provides valuable time-coherent and spatially coherent information. This optical approach will be enhanced by the use of non-invasive measures of metabolic activity, such as peripheral tissue oxygen consumption by magnetic resonance imaging, as well as high-throughput screening of blood and tissue metabolites (metabolomics). Dr. Panagia proposes to extend the investigation to include multiple models of heart failure of different etiologies and to examine, in more detail, the energetic features that underlie the transition from compensated to decompensated heart failure. In summary, by bringing together cutting edge technology and a well-rounded team of experts in the context of a well-defined research plan and mentorship structure, Dr. Panagia will be able to synergistically merge the fields of advanced imaging and energy metabolism to elucidate novel mechanisms that underlie cardiac pathophysiology and elaborate the skills essential for him to become an independent investigator.