Novel pathways modulating Raf-mediated cardiac hypertrophy

调节 Raf 介导的心脏肥大的新途径

• 批准号: 8611966
• 负责人: Matthew J Wolf
• 金额: $ 38.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611966
• 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; Heart Hypertrophy; Heart failure; Human; Hyperplasia; Hypertrophy; In Vitro; Individual; Knock-in Mouse; Knock-out; Lead; MAP2K1 gene; MAP2K1 gene; Mammals; Mediating; 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; public health relevance; 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）：心脏肥大和进展为明显的心力衰竭与显着的发病率和死亡率相关。然而，心血管疾病的哺乳动物模型对于研究心脏生理学和信号通路非常有帮助。这些模型不太适合大规模的遗传筛选。因此，开发了使用果蝇作为模型来识别引起或改变心肌病的新基因的策略，以规避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）对于维持成年果蝇正常的发育后心脏功能是必需的。此外，EGFR 的激活以及随后向小 GTP 酶、Ras 以及激酶、Raf 和 MEK1 发出的信号，会导致果蝇和哺乳动物的心脏肥大。通过激酶 Hippo 发出的信号会改变共转录激活剂 yorkie 的活性，并且还会产生类似于果蝇中 EGFR/Ras/Raf 通路的心脏肥大。长期目标是利用果蝇遗传学作为发现平台，了解调节心脏肥大和扩张型心肌病发生和进展的分子信号，并将这些发现转化为人类。该应用的总体目标是检查 Raf-MEK1 通路和 yorkie 在心脏肥大中的激活。中心假设是 Raf-MEK1 和 Hippo-YAP1 通路之间的串扰驱动心肌细胞决定肥大或增生。 将检查以下具体目标以检验中心假设：（1）确定 Raf-MEK1 介导的心脏肥大是否通过调节果蝇中的 Hippoyorkie 通路而发生，并确定在 yorkie 下游起作用的信号通路。 (2) 鉴定哺乳动物YAP1中驱动心肌细胞肥大或增殖的特定模块结构域； (3)确定YAP-1的减少是否会改变TAC诱导的压力超负荷后RafL613V/+敲入小鼠或野生型小鼠的心脏肥大或心力衰竭的严重程度。该提案的创新之处在于，它利用果蝇快速识别两条进化上保守的信号通路中的新分子，并将这些发现转化为哺乳动物。该提案预计将鉴定出以前未知的改变 Raf 依赖性心脏肥大的成分，并更好地了解驱动人类病理性肥大的途径。