Genetics and Treatment of Heart Failure in the Young

描述(由申请人提供)： 儿童心力衰竭可由先天性或获得性心肌损伤引起。这项计划项目资助申请的重点是研究年轻人心力衰竭的起源和治疗。拟议的研究将确定转录因子的异常表达如何导致导致心力衰竭的形态发生异常(项目1)，确定ROCK1促凋亡信号转导通路的调节可以在多大程度上防止导致儿童心力衰竭的损伤后心肌细胞死亡(项目2)，以及可以在多大程度上操纵心脏保护性细胞因子途径和增生性生长计划来挽救高危心肌和/或促进导致儿童心力衰竭的损伤后受损心肌组织的再生(项目3)。这些项目在主题上是相互联系的，因为他们研究了基因表达、细胞生存和细胞生长途径在心力衰竭的起源中是如何相互关联的，以及如何将这些途径的操纵用于治疗。除了这一专题整合外，这些项目在技术上也是相互联系的，因为将利用共同的方法、方法和试剂，从而迅速加快发现的步伐。此外，在一个项目中开发的遗传和获得性损伤模型和/或治疗干预措施将用于该应用程序内其他项目的概念验证研究，从而加快潜在的发现转化。还应指出的是，这三个项目中的每个项目都代表着两名具有互补技能和专门知识的资深调查人员所做的同等而重大的贡献，其中一人担任项目负责人，另一人担任合作调查员。因此，计划项目赠款申请将把赫尔曼·B·威尔斯儿科研究中心心脏发育生物学计划内的六个实验室的活动整合为一个统一的主题，从而进一步提高研究的速度和生产率，以满足一个重要的和未得到满足的临床需求，即儿童心力衰竭的研究和治疗。

DESCRIPTION (provided by applicant): Heart failure in children can result from congenital or acquired injury to the myocardium. This Program Project Grant application is focused on studying the origins and treatment of heart failure in the young. The proposed studies will establish how aberrant expression of transcription factors can give rise to morphogenic anomalies that contribute to heart failure (Project 1), establish the degree to which modulation of the ROCK1 pro-apoptotic signal transduction pathway can protect against cardiomyocyte death following injuries which induce childhood heart failure (Project 2), and establish the extent to which cardioprotective cytokine pathways and hyperplastic growth programs can be manipulated to salvage at-risk myocardium and/or promote regeneration of damaged myocardial tissue following injuries which induce childhood heart failure (Project 3). The projects are thematically linked in that they examine how gene expression, cell survival and cell growth pathways are interrelated in the origins of heart failure, and furthermore how manipulation of these pathways can be exploited therapeutically. In addition to this thematic integration, the projects are technically linked in that common methodologies, approaches, and reagents will be utilized, thereby rapidly accelerating the pace of discovery. Moreover, genetic and acquired injury models and/or therapeutic interventions developed in one project will be used for proof-of-concept studies in other projects within the application, thereby accelerating the potential translation of discoveries. It should also be noted that each of the three projects represents an equal and significant contribution of effort from two established investigators having complementary skills and expertise, with one serving as Project Leader and the other as Collaborating Investigator. Thus, the Program Project Grant application will integrate the activities of six laboratories within the Cardiac Developmental Biology Program in the Herman B Wells Center for Pediatric Research with a unifying theme, thereby further enhancing the pace and productivity of research for an important and unmet clinical need, namely the study and treatment of heart failure in children.