Novel pathways modulating Raf-mediated cardiac hypertrophy

调节 Raf 介导的心脏肥大的新途径

• 批准号: 9097132
• 负责人: Matthew J Wolf
• 金额: $ 23.89万
• 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/9097132
• 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 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）：心脏肥大和向明显的心力衰竭发展与显着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和信号通路非常有帮助。这些模型不容易适应大型遗传筛查。因此，制定了使用果蝇作为模型来识别引起或修改心肌病的新基因的策略，以规避与心血管疾病哺乳动物模型相关的某些复杂性。 表皮生长因子受体（EGFR）对于维持成年果蝇的正常发育后心脏功能是必要的。此外，EGFR的激活以及随后的信号向小的GTPase，RAS和激酶RAF和MEK1激活，引起苍蝇和哺乳动物的心脏肥大。河马通过激酶发出信号，改变了共转录激活剂约克的活性，并且还会产生类似于蝇中EGFR/RAS/RAF途径的心肥力。长期目标是了解使用果蝇遗传学作为发现平台并将发现转化为人类的分子信号，该分子信号调节心脏肥大和扩张心肌病的发展和扩张性心肌病。该应用程序的总体目标是检查RAF-MEK1途径和心脏肥大中约克的激活。中心假设是RAF-MEK1和HIPPO-YAP1途径之间的串扰将心肌细胞的决策推向肥大或增生。 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苍蝇的河马 - 约克途径并确定约克下游功能的信号通路。 （2）确定驱动心肌肥大或增殖的哺乳动物YAP1中的特定模块化结构域； （3）确定YAP-1的降低是否会改变RAFL613V/+敲门小鼠中心脏肥大或心力衰竭的严重程度，或者在TAC诱导的压力超负荷后，是否会改变YAP-1。该建议在使用果蝇在两个进化保守的信号通路中迅速鉴定出新的分子并将这些发现转化为哺乳动物。该建议有望确定以前未知的成分，这些成分改变了RAF依赖性心脏肥大，并可以更好地理解驱动人类病理肥大的途径。