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Myocardial Physiology of Growth Differentiation Factor Signaling

生长分化因子信号传导的心肌生理学

基本信息

批准号：
10711086
负责人：
RICHARD T LEE
金额：
$ 60.85万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711086
关键词：
Address Affect Age Aging American Amino Acid Sequence Amino Acids Biochemical Biochemistry Biological Markers Blood CRISPR/Cas technology Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cessation of life Clinical Data Collaborations Coronary Coronary heart disease Data Differentiation and Growth Disease Event Future GDF11 gene GDF8 gene Genetically Engineered Mouse Growth Healthcare Heart Heart Diseases Heart Hypertrophy Hospitals Human Human Biology In Vitro Laboratories Ligands MADH2 gene Maintenance Mass Spectrum Analysis Measurement Measures Molecular Mus Muscle Development Muscle function Myocardial Myocardium Outcome Pathway interactions Patients Phenotype Physiological Physiology Proteins Publishing Receptor Signaling Role Signal Pathway Signal Transduction Skeletal Development Structural Biochemistry Structure System Systems Development Techniques Testing Transforming Growth Factor beta Translating Universities Woman X-Ray Crystallography cell growth cohort experimental study extracellular functional outcomes genomic locus heart dimension/size heart function human data human disease in vivo insight interest laboratory experiment loss of function mutation member morphogens mortality outcome prediction pressure prospective

项目摘要

SUMMARY: Myocardial Physiology of Growth Differentiation Factor Signaling GDF11 and the closely related protein GDF8 (also known as myostatin) can regulate cardiac hypertrophy. We now have new prospective data in a large cohort of coronary heart disease patients showing that low blood levels of subforms of GDF8 and GDF11 powerfully predict future all-cause mortality. These new data point to specific forms of GDF11 and GDF8 as critical factors in heart disease. Furthermore, human loss- of-function mutations in GDF11 have now been identified that cause multi-system disease, including cardiovascular disease, showing the importance of GDF11 in human biology. GDF11 and GDF8 are members of the transforming growth factor β (TGFβ) superfamily of extracellular ligands and were initially thought to serve similar or redundant roles due to protein sequence identity (90% identical) within their mature signaling domains. We recently collaborated with multiple other laboratories to determine that mature GDF11 is a significantly more potent activator of SMAD2/3 dependent signaling than GDF8 in vitro, likely due to better utilization of key signaling receptors. Moreover, through x-ray crystallography-guided biochemical experiments, we identified key amino acids of the two ligands responsible for their differences in potency. These findings support the concept that GDF11 and GDF8 are likely not functionally equivalent, especially when ligand concentrations are low, as exist in vivo. However, it is not yet understood if differences in GDF11 and GDF8 at the molecular level translate to distinct functional outcomes and pathway activation in vivo. Defining the roles of these ligands in vivo can best be addressed by genetically engineered mice. Using CRISPR technology, we have now generated three new lines of mice with specific changes guided by our structural and biochemical studies on GDF11 vs. GDF8 to address this Project’s three Aims. This project will uncover the biochemistry of these ligands in vivo while retaining regulatory structure of the endogenous genomic loci. Importantly, we have already used Targeted Locus Amplification to prove that we have edited only the intended amino acids in all three of the new lines of mice. Using these newly generated mice, we will pursue the following Aims: Aim 1. To test the hypothesis that introducing the mature domain of GDF11 into the myostatin (GDF8) locus regulates cardiac size and function using Gdf8Gdf11swap mice. Aim 2. To test the hypothesis that gain of potency in GDF8 with two specific amino acids from GDF11 regulates cardiac muscle growth in mice (Gdf8G89D/E91Q mice). Aim 3. To test the hypothesis that GDF11 potency is required to maintain cardiac muscle function in vivo under pressure overload using chimeric mice with specific amino acids from GDF8 introduced into mature GDF11 (Gdf11D89G/Q91E mice).

摘要：生长分化因子信号传导的心肌生理学