Cardiolipin Biosynthesis and Mitochondrial Energy Production in Pediatric Idiopathic Dilated Cardiomyopathy

 描述（由申请人提供）：本提案描述了一个为期5年的培训计划，旨在发展儿科心力衰竭领域的学术生涯。主要研究者拥有MD、Ph.D.在费城儿童医院完成了儿科和遗传学的临床住院医师培训，最近在科罗拉多大学完成了儿科心脏病学的奖学金培训。在临床培训期间，她 对儿童心力衰竭（HF）的病因产生了兴趣，并发起了一项研究 在Brian Stauffer博士的主要指导下进行。拟议的研究计划将是第一个提供儿童特发性扩张型心肌病（IDC）线粒体功能和能量代谢的全面表征。该项目解决了代表性不足和脆弱人群中的关键医疗差距：儿童从成人HF治疗的进步中获益甚少。这项工作的目标是通过识别IDC儿童心肌中独特的病理生理过程来影响儿童心力衰竭的结局，从而确定针对儿科疾病的饮食和药物治疗。导师团队提供心血管生物学方面的多样化培训背景和研究专业知识。每个成员都是由外部资助的，是儿科心力衰竭和心血管生理学领域的领导者，并致力于他们作为研究导师的角色。初步研究表明，在儿科IDC的线粒体含量，磷脂含量和能量能力的变化的证据。本研究将通过分析应激和生物发生反应以及使用人体组织直接测定电子传递链和脂肪酸内流的介体来进一步表征线粒体功能障碍。通过异丙肾上腺素（ISO）治疗幼年小鼠，重现了小儿HF的特征。提出该模型作为进一步描述儿科HF中线粒体能量利用改变的机制的模型。儿科在科罗拉多丹佛大学提供了一个理想的环境，通过整合专业知识和资源，从临床和基础科学部门在整个科罗拉多系统的大学培训医生，科学家。这种环境，与访问一个大型的人类心脏组织库和主要研究者的导师团队非常适合，以确保一个新的研究领域的成功，在转化医学的职业生涯可以构建。

 DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of an academic career in the field pediatric heart failure. The principal investigator has MD, Ph.D. training, completed clinical residency training in Pediatrics and Genetics at the Children's Hospital of Philadelphia, and recently completed fellowship training in Pediatric Cardiology at the University of Colorado. During this period of clinical training she has developed an interest in the etiologies of heart failure (HF) in children, and initiated a research program under the primary mentorship of Dr. Brian Stauffer. The proposed research program will be the first to provide a thorough characterization of mitochondrial function and energy metabolism in pediatric idiopathic dilated cardiomyopathy (IDC). The project addresses a critical healthcare disparity in an under-represented and vulnerable population: children who have received little benefit from advances in adult HF treatments. The goal of the work is to impact outcomes of heart failure in children through identification of unique pathophysiologic processes in myocardium of children with IDC, allowing identification of dietary and pharmacologic therapies tailored to pediatric disease. The mentorship team provides a diverse training backgrounds and research expertise in cardiovascular biology. Each member is extramurally funded, a leader in the field of pediatric heart failure and cardiovascular physiology, and committed to their role as research mentors. Preliminary work has demonstrated evidence of changes in mitochondrial content, phospholipid content, and energy capacity in pediatric IDC. This research will focus on further characterization of mitochondrial dysfunction through analysis of stress and biogenesis responses and direct assay of the electron transport chain and mediators of fatty-acid influx for ß-oxidation using human tissue. Features of pediatric HF are recapitulated by treatment of a juvenile mouse with isoproterenol (ISO). This model is proposed as a model to further delineate the mechanisms of altered mitochondrial energy utilization in pediatric HF. The Department of Pediatrics at the University of Colorado Denver provides an ideal setting for training physician-scientists by incorporating expertise and resources from Clinical and Basic Science Departments throughout the University of Colorado System. This environment, with access to a large human heart tissue bank and the principal investigator's mentorship team are ideally suited to ensure the success of a novel area of research upon which a career in translational medicine can be constructed.