Hippo and Wnt signaling in cardiac regeneration

Hippo 和 Wnt 信号在心脏再生中的作用

• 批准号: 9398155
• 负责人: James F Martin
• 金额: $ 49.93万
• 依托单位: TEXAS HEART INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398155
• 关键词: Acute; Address; Adrenergic Agents; Adult; Binding; Biochemical; Biology; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiac Output; Cause of Death; Cell Line; Cell Nucleus; Cessation of life; Chronic; Cicatrix; Clinical; DNA Binding; Data; Development; Event; Excision; Exclusion; Financial compensation; Functional disorder; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Grant; Heart; Heart Rate; Heart failure; Infarction; Injury; Knock-in Mouse; Knowledge; Lead; Lysine; Measurable; Methods; Modification; Molecular; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Oxygen Consumption; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Property; Publishing; Pump; Recovery; Regulation; Regulatory Pathway; Reporting; Residual state; Secondary to; Serine; Signal Pathway; Signal Transduction; Source; Survival Rate; System; Technology; Testing; Time; Tissues; Translations; Ubiquitination; United States; WNT Signaling Pathway; Work; base; cardiac regeneration; cardiac repair; cardiogenesis; cofactor; effective therapy; experimental study; gain of function; genome editing; heart cell; heart damage; heart dimension/size; heart function; improved; inhibitor/antagonist; innovation; insight; mortality; mutant; novel; prevent; protein protein interaction; public health relevance; repaired; self-renewal; sumo1 gene; transcription factor

 DESCRIPTION (provided by applicant): This R01 application will investigate a novel signaling pathway, the Hippo pathway, in mammalian heart regeneration. The long-term goal is to develop new treatments for patients with heart failure by generating new cardiomyocytes in the adult heart. The objectives of this application are to gain insight into molecular properties of cardiac tissue that are regulated by Hippo signaling. The central hypothesis is that Hippo signaling is a negative regulatory pathway that prevents cardiomyocyte regeneration in the adult mammalian heart. The specific aims are to determine whether the Hippo and Wnt pathways regulate adult heart regeneration in a manner similar to the interaction in heart development; to determine whether the sumoylation post-translation modification is an important mechanism in Yap regulation; and to determine whether Hippo functions in the context of a chronic scar after myocardial infarction. The project is conceptually and technically innovative. Concepts to be tested include new ideas in cardiomyocyte biology and cutting edge genome editing technologies to address hypotheses. The significance is high because there are no treatments for heart failure due to cardiomyocyte loss. Devising ways to generate new cardiomyocytes is highly significant.

 描述（由申请人提供）：该 R01 申请将研究哺乳动物心脏再生中的一种新的信号传导途径，即 Hippo 途径。长期目标是通过在成人心脏中产生新的心肌细胞来开发治疗心力衰竭患者的新疗法。该应用的目的是深入了解受 Hippo 信号传导调节的心脏组织的分子特性。中心假设是 Hippo 信号传导是一种负调节途径，可阻止成年哺乳动物心脏中的心肌细胞再生。具体目标是确定 Hippo 和 Wnt 通路是否以类似于心脏发育中相互作用的方式调节成人心脏再生；确定sumoylation翻译后修饰是否是Yap调控的重要机制；并确定 Hippo 是否在心肌梗塞后慢性疤痕的情况下发挥作用。该项目在概念和技术上都具有创新性。待测试的概念包括心肌细胞生物学的新想法和解决假设的尖端基因组编辑技术。由于心肌细胞丢失导致的心力衰竭尚无治疗方法，因此意义重大。设计产生新心肌细胞的方法非常重要。