Functional Validation of Myh14 in Stress-Induced Cardiac Remodeling.

Myh14 在应激诱导的心脏重塑中的功能验证。

• 批准号: 9751944
• 负责人: Jessica J Wang
• 金额: $ 17.51万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751944
• 关键词: Affect; Animals; Apoptosis; Area; Autophagocytosis; Bioinformatics; Biological; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cell Death; Cell Size; Cell Survival; Cells; Cellular biology; Chronic; Complex; Control Locus; Data; Data Analyses; Diagnosis; Dimensions; Disease; Doctor of Philosophy; Echocardiography; Environmental Risk Factor; Exhibits; FOXO1A gene; Fibrosis; Fostering; Gene Proteins; Genes; Genetic; Genetic Models; Genetic Techniques; Genetic Transcription; Genetic Variation; Genomics; Goals; Hand; Health; Health Care Costs; Heart; Heart Injuries; Heart failure; Hospitalization; Human; Human Genome; Hybrids; Hypertrophy; In Vitro; Inbred Strains Mice; Individual; Infusion procedures; Intercalated disc; Isoproterenol; K-Series Research Career Programs; Knockout Mice; Knowledge; Lead; Left; Left Ventricular Hypertrophy; Left Ventricular Mass; MYC gene; Maps; Measures; Mentors; Mentorship; Modeling; Molecular; Molecular Biology; Mus; Myosin ATPase; National Heart, Lung, and Blood Institute; Organ; Pathologic; Pathology; Pathway interactions; Phase; Phenotype; Physicians; Physiological; Physiology; Play; Population; Predisposition; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Quantitative Trait Loci; Research; Research Personnel; Research Project Grants; Role; Scientist; Secondary to; Series; Signal Transduction; Stress; Structure; System; Systems Biology; Techniques; Testing; Therapeutic; Training Programs; United States National Institutes of Health; Validation; Ventricular; WNT Signaling Pathway; Work; base; beta catenin; biological adaptation to stress; cohort; driving force; genetic approach; genetic makeup; genetic resource; genome wide association study; genome-wide; improved; in vivo; insight; knockout animal; knockout gene; lifestyle factors; loss of function; mechanotransduction; mouse model; non-muscle myosin; novel; novel strategies; outcome forecast; programs; response; success; trait; transcriptome

PROJECT SUMMARY / ABSTRACT Heart failure, a leading cause of hospitalization and one of the primary driving forces behind rising healthcare costs, is a complex disease that is a result of the interplay among multiple genes in combination with lifestyle and environmental factors. Previous large-scale human genome-wide association studies to identify genetic variation underlying the heart failure disease spectrum have yielded limited insights. As part of my PhD thesis, we turned to a systems genetics resource, called the Hybrid Mouse Diversity Panel, to characterize cardiac structural and functional changes under chronic isoproterenol stress over 3 weeks. We identified Myh14 as a top candidate for left ventricular mass hypertrophy. Using a genetically modified Myh14 knockout mouse line, we validated Myh14 as a novel modifier gene for left ventricular hypertrophy secondary to chronic isoproterenol stimulation. This proposal describes a five-year mentored physician-scientist training program to further define the role of Myh14 in stress-induced cardiac remodeling. We hypothesize that Myh14 is a negative regulator of hypertrophy. Based on prioritization using systems genetics and experimental findings, we have outlined a series of molecular biology, cell biology, and mouse genetics approaches to test whether Myh14 deficiency leads to alteration in hypertrophic, Wnt/β-catenin and FOXO1 signaling. The proposed research will provide fundamental insights into how Myh14 modulates stress-induced cardiac remodeling and open a new understanding of how common genetic variation plays a role in stress-induced cardiac remodeling. The outlined program will allow the candidate to develop a mastery in the functional validation of novel candidate genes in cardiac remodeling using molecular biology, cell biology and mouse genetics techniques towards the long-term goal of understanding how genetic variation modifies cardiovascular disease in humans. The intensive research plan will allow the candidate to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator. The aims of this project are aligned with the major strategic goal of NIH and NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.

项目摘要 /摘要 心力衰竭，住院的主要原因，以及医疗保健崛起的主要动力之一 成本是一种复杂的疾病，是多个基因与生活方式结合的相互作用的结果 和环境因素。以前的大型人类基因组关联研究以鉴定遗传 心力衰竭疾病频谱的变异产生了有限的见解。作为我博士学位论文的一部分， 我们转向了一个系统的遗传资源，称为混合小鼠多样性面板，以表征心脏 在3周内，慢性异丙肾上腺素应激下的结构和功能变化。我们将MYH14确定为 左心室质量肥大的最高候选者。使用转基因的MYH14敲除鼠标线， 我们验证了MYH14作为继发于慢性异丙肾上腺素的左心室肥大的新型修饰剂基因 刺激。 该提案描述了一项为期五年的身体科学家培训计划，以进一步定义 MYH14在压力引起的心脏重塑中。我们假设MYH14是 肥大。基于使用系统遗传学和实验发现的优先级，我们概述了一个 一系列分子生物学，细胞生物学和小鼠遗传学方法测试MYH14缺乏症是否缺乏 导致肥厚，Wnt/β-catenin和FoxO1信号的改变。拟议的研究将提供 关于MYH14如何调节压力引起的心脏重塑的基本见解并打开新的 了解常见遗传变异如何在压力诱导的心脏重塑中起作用。 概述的程序将使候选人能够在新颖的功能验证中掌握掌握 使用分子生物学，细胞生物学和小鼠遗传学技术的心脏重塑中的候选基因 朝着了解遗传变异如何改变人类心血管疾病的长期目标。 密集的研究计划将使候选人能够启动该研究项目，同时拥有 为了将目标置于独立研究者的目标所需的必要精神和支持。这 该项目的目标与NIH和NHLBI的主要战略目标保持一致，以提高我们对 健康和疾病的分子和生理基础。