Novel pathways modulating Raf-mediated cardiac hypertrophy

调节 Raf 介导的心脏肥大的新途径

• 批准号: 9001357
• 负责人: Matthew J Wolf
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001357
• 关键词: Abnormal Cell; Address; Adult; Affect; Amino Acid Motifs; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cell Count; Cell Size; Complex; Development; Dilated Cardiomyopathy; Drosophila genus; Embryo; Epidermal Growth Factor Receptor; Fruit; Genes; Genetic; Genetic Screening; Goals; Health; Heart Hypertrophy; Heart failure; Human; Hyperplasia; Hypertrophy; In Vitro; Individual; Knock-in Mouse; Knock-out; Lead; MAP2K1 gene; Mammals; Mediating; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Muscle Cells; Organ Size; Orthologous Gene; Pathologic; Pathway interactions; Phosphotransferases; Physiology; Proteins; Ras/Raf; Receptor Signaling; Regulation; Role; Severities; Signal Pathway; Signal Transduction; Testing; Transcription Coactivator; Translating; Ventricular; Wild Type Mouse; Work; base; cell growth; fly; in vivo; innovation; mortality; novel; pressure; raf Kinases

DESCRIPTION (provided by applicant): Cardiac hypertrophy and progression to overt heart failure is associated with significant morbidity and mortality. Mammalian models of cardiovascular disease are tremendously helpful to study cardiac physiology and signaling pathways, however; these models are not readily amenable to large genetic screens. Therefore, strategies using Drosophila as model to identify new genes that cause or modify cardiomyopathies were developed to circumvent some of the complexities associated with mammalian models of cardiovascular disease. The epidermal growth factor receptor (EGFR) is necessary to maintain normal post- developmental cardiac function in adult Drosophila. Moreover, the activation of EGFR and subsequent signals to the small GTPase, Ras, and the kinases, Raf and MEK1, cause cardiac hypertrophy in flies and mammals. Signaling through the kinase, Hippo, alters the activity of the co-transcriptional activator, yorkie, and also produces cardiac hypertrophy similar to the EGFR/Ras/Raf pathway in flies. The long-term goal is understand the molecular signals that modulate the development and progression of cardiac hypertrophy and dilated cardiomyopathy using Drosophila genetics as a discovery platform and translate the findings to humans. The overall objective for this application is to examine the Raf-MEK1 pathway and the activation of yorkie in cardiac hypertrophy. The central hypothesis is that crosstalk between the Raf-MEK1 and Hippo-YAP1 pathways drives cardiomyocyte decisions towards hypertrophy or hyperplasia. The following Specific Aims will be examined to test the central hypothesis: (1) Determine whether Raf-MEK1-mediated cardiac hypertrophy occurs via regulation of the Hippo- yorkie pathway in flies and identify signaling pathways that function downstream of yorkie.; (2) Identify the specific modular domains in mammalian YAP1 that drive cardiomyocyte hypertrophy or proliferation; and (3) Determine whether a reduction in YAP-1 modifies the severity of cardiac hypertrophy or heart failure in RafL613V/+ knock-in mice or wild-type mice after TAC-induced pressure overload. This proposal is innovative in its use of Drosophila to rapidly identify novel molecules in two evolutionarily conserved signaling pathways and translate these findings to mammals. The proposal is expected to identify previously unknown components that modify Raf-dependent cardiac hypertrophy and lead to better understanding of pathways that drive pathologic hypertrophy in humans.

描述(由申请人提供)：心肌肥大和进展为明显的心力衰竭与显著的发病率和死亡率有关。然而，心血管疾病的哺乳动物模型对研究心脏生理学和信号通路有极大的帮助；这些模型不容易受到大的遗传筛选的影响。因此，使用果蝇作为模型来识别导致或修改心肌病的新基因的策略被开发出来，以绕过与哺乳动物心血管疾病模型相关的一些复杂性。表皮生长因子受体(EGFR)是维持成年果蝇正常发育后心脏功能所必需的。此外，EGFR的激活和随后的小GTP酶RAS以及Raf和MEK1激酶的信号会导致果蝇和哺乳动物的心肌肥大。河马通过该激酶发出信号，改变共转录激活剂York kie的活性，并产生类似于果蝇的EGFR/RAS/Raf途径的心肌肥厚。长期目标是利用果蝇遗传学作为发现平台，了解调控心肌肥大和扩张型心肌病发展和进展的分子信号，并将发现转化为人类。这项应用的总体目标是研究Raf-MEK1通路和约克在心肌肥厚中的激活。中心假设是Raf-MEK1和Hippo-YAP1通路之间的串扰促使心肌细胞决定肥大或增殖。将检验以下特定目标来检验中心假说：(1)确定Raf-MEK1介导的心肌肥厚是否在果蝇中通过调节河马-York kie途径发生，并确定起作用的约克下游的信号通路；(2)确定哺乳动物YAP1中驱动心肌细胞肥大或增殖的特定模块结构域；以及(3)确定YAP-1的减少是否改变了TAC诱导的压力超负荷后RafL613V/+敲打小鼠或野生型小鼠心肌肥厚或心力衰竭的严重程度。这一提议的创新之处在于，它使用果蝇来快速识别两个进化上保守的信号通路中的新分子，并将这些发现翻译到哺乳动物身上。该提案有望识别先前未知的改变Raf依赖的心肌肥大的成分，并导致更好地理解推动人类病理性肥厚的途径。