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: 9388279
• 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/9388279
• 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; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Techniques; Genetic Transcription; Genetic Variation; Genomics; Goals; Hand; Health; Health Care Costs; Heart; Heart failure; Hospitalization; Human; Human Genome; Hybrids; Hypertrophy; In Vitro; Inbred Strains Mice; Individual; Infusion procedures; Injury; 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