Cardiolipin Biosynthesis and Mitochondrial Energy Production in Pediatric Idiopathic Dilated Cardiomyopathy

 描述(由申请者提供)：这份建议书描述了一项为期5年的培训计划，旨在为儿童心力衰竭领域的学术生涯发展奠定基础。这位首席研究员接受过医学博士培训，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研究员培训。在这段时间的临床培训中，她有 对儿童心力衰竭(HF)的病因产生了兴趣，并发起了一项研究 在布赖恩·施陶弗博士的主要指导下进行的计划。这项拟议的研究计划将首次对儿童特发性扩张型心肌病(IDC)的线粒体功能和能量代谢进行彻底的表征。该项目解决了代表性不足和脆弱人口中的一个严重的医疗差距：儿童几乎没有从成人心力衰竭治疗的进步中受益。这项工作的目标是通过确定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量身定做的饮食和药物治疗方法。导师团队在心血管生物学方面提供不同的培训背景和研究专业知识。每个成员都得到了外部资助，是儿科心力衰竭和心血管生理学领域的领导者，并致力于发挥他们作为研究导师的作用。初步工作已经证明，儿科IDC的线粒体含量、磷脂含量和能量能力发生了变化。这项研究将集中于通过分析应激和生物发生反应以及利用人体组织直接分析电子传输链和脂肪酸内流的介体来进一步表征线粒体功能障碍。通过用异丙肾上腺素(ISO)治疗一只幼年小鼠，概括了儿童心衰的特征。这一模型被提出作为进一步描述儿童心衰时线粒体能量利用改变的机制的模型。科罗拉多大学丹佛分校的儿科系整合了科罗拉多大学整个系统临床和基础科学系的专业知识和资源，为培训内科科学家提供了理想的环境。这种环境，有一个大型的人体心脏组织库和首席研究员的指导团队，非常适合确保一个新的研究领域的成功，在此基础上可以建立在转化医学的职业生涯。

 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.