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Mechanisms of Cu-binding factors to promote myogenic gene expression

铜结合因子促进生肌基因表达的机制

基本信息

批准号：
10618921
负责人：
Teresita Del Nino Jesus Padilla-Benavides
金额：
$ 36.15万
依托单位：
WESLEYAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618921
关键词：
Affect Ataxia Binding Binding Sites Biochemical Biochemical Reaction Biology Cardiac Categories Cell Differentiation process Cell Lineage Cell Nucleus Cell Proliferation Cell physiology Cells Cellular Stress ChIP-seq Chromatin Chromatin Structure Coenzymes Complex Copper Coupled Culture Media Data Deficiency Diseases Development Developmental Process Differentiation Antigens Disease Dystonia Enzymes Excretory function Failure Family Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomic DNA Growth Health Hepatolenticular Degeneration Homeostasis Human Hydroxyl Radical Hypertrophic Cardiomyopathy Immunoprecipitation Impairment Ions Knock-out Knowledge Life Location Mass Spectrum Analysis Menkes Kinky Hair Syndrome Metabolism Metals Mitochondria Modeling Modification Molecular Molecular Chaperones Mus Muscle Muscle Development Muscle hypotonia Mutation Myoblasts Myogenin Myopathy Neurologic Neutropenia Organ Pathologic Pathology Patients Peptide Sequence Determination Peripheral Nervous System Diseases Phenotype Play Proliferating Proliferation Marker Property Proteins Regulation Role Skeletal Muscle Specific qualifier value Study models Techniques Testing Time Tissue Differentiation Tissue-Specific Gene Expression Tissues Trace Elements Trace metal Transcriptional Regulation Western Blotting absorption cofactor expectation experimental study genomic locus in vivo iron absorption knock-down mouse model myogenesis novel posttranscriptional prevent programs promoter recruit satellite cell skeletal muscle differentiation transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY Cell development and differentiation require lineage specific mechanisms by which cells initiate programs of gene expression. In normal conditions, lineage determination involves activation of genes that are transcriptionally silent by specific transcription factors, chromatin remodelers, coactivators, and other lineage specific molecules. Skeletal muscle differentiation is an excellent model for studying fundamental principles of tissue-specific gene expression and differentiation as there is a significant understanding of mechanisms controlling myogenic-specific gene expression. However, emerging evidence shows a novel category of Copper (Cu)-binding factors that may have a previously unappreciated direct impact in the regulation of myoblast proliferation and differentiation. Cu is an essential trace metal that serves as a catalytic co-factor for a wide variety of enzymatic reactions that play critical roles in life. Cu deficiency and overload leads to pathophysiological conditions including Menkes and Wilson’s diseases, neutropenia, impaired iron absorption, peripheral neuropathy, mitochondrial deficiencies and hypertrophic cardiomyopathy. Therefore, the mechanisms for Cu distribution and usage in different tissues and organs, as well as the consequences due to dysregulated Cu acquisition, are important to human health. Limited information is available regarding Cu and Cu-binding factors and their mechanisms of action in myogenesis and most developmental processes. We propose to elucidate novel mechanisms of gene regulation that drive muscle differentiation and development and that are dependent on copper and Cu-binding transcription factors. We propose integrative studies that combine diverse molecular, biochemical and spectroscopic techniques to characterize novel molecular mechanisms by which Cu-binding factors regulate myogenic differentiation. We propose a novel model where Cu controls myogenesis by activating Cu-TFs that may act synchronously, either by acting on different promoters at the same time or by acting sequentially at different stages of differentiation, or both. Our experiments will identify new components and mechanisms for mammalian Cu-binding factors in the regulation of lineage-specific gene expression. Our studies also will establish a basis for understanding muscular diseases related to aberrant Cu biology using well-characterized mouse models for Menkes and Wilson’s diseases. Understanding the molecular mechanisms that drive lineage specific gene expression dependent on Cu will greatly advance our knowledge of several Cu-related diseases.

项目总结细胞的发育和分化需要特定的细胞启动程序的机制关于基因表达的。在正常情况下，血统决定涉及到激活特定转录因子、染色质重构体、共激活子和其他谱系的转录沉默特定的分子。骨骼肌分化是研究骨骼肌分化基本原理的极佳模型。由于对组织特异性基因表达和分化机制有重要的了解控制生肌特异性基因的表达。然而，新出现的证据表明，一种新的类别铜(铜)的结合因素可能会在调节中产生以前未被认识到的直接影响成肌细胞的增殖和分化。铜是一种必需的痕量金属，可作为多种酶反应的催化辅因子。在生活中扮演关键角色的人。铜缺乏和超负荷会导致病理生理状况，包括门克斯和威尔逊病，中性粒细胞减少，铁吸收受损，周围神经病变，线粒体缺乏症和肥厚型心肌病。因此，铜在土壤中的分布和利用机制不同的组织和器官，以及铜摄取失调造成的后果，对人类健康。有关铜和铜结合因子及其机制的信息有限。在肌肉发生和大多数发育过程中的作用。我们建议阐明基因的新机制。驱动肌肉分化和发育的调控以及依赖于铜和铜结合的调控转录因子。我们建议进行综合研究，结合不同的分子、生化和用光谱技术表征铜结合因子调控的新分子机制肌源性分化。我们提出了一种新的模型，其中铜通过激活铜-转铁蛋白来控制肌肉发生可以通过同时作用于不同的启动者或通过在分化的不同阶段，或者两者都有。我们的实验将确定新的组件和机制哺乳动物铜结合因子对谱系特异性基因表达的调节。我们的研究也将为了解与铜生物异常相关的肌肉疾病奠定基础孟克斯和威尔逊病的小鼠模型。了解驱动血统的分子机制依赖于铜的特异性基因表达将极大地促进我们对几种铜相关疾病的认识。