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Epigenetic dysregulation of muscle differentiation in Kabuki syndrome

歌舞伎综合征肌肉分化的表观遗传失调

基本信息

批准号：
10560603
负责人：
EMANUELA GUSSONI
金额：
$ 53万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-02 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560603
关键词：
ATAC-seq Address Adult Affect Automobile Driving Cardiac Cells Clinical Complex Data Defect Development Developmental Delay Disorders EZH2 gene Embryonic Development Enhancers Epigenetic Process Etiology Exhibits Fiber Functional disorder Gene Expression Gene Targeting Genes Genetic Transcription Goals Heterogeneity Heterozygote Histones Human Impairment Individual Intellectual functioning disability Kabuki Make-Up Syndrome Kidney Knowledge Life Link Methyltransferase Modeling Molecular Target Mus Muscle Muscle Fatigue Muscle Fibers Muscle function Muscle hypotonia Muscle satellite cell Muscular Atrophy Mutant Strains Mice Mutate Mutation Myosin ATPase Neural Conduction Organ Pathogenicity Patient Care Patients Phenotype Proteins Rare Diseases Repression Role Secondary to Severities Signal Transduction Skeletal Muscle Specific qualifier value Symptoms System Tissues Work epigenomics experimental study gene network hearing impairment improved loss of function mouse model muscle form postnatal promoter protein complex reduced muscle strength satellite cell stem cell differentiation stem cell self renewal transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Kabuki Syndrome (KS) is a rare disease caused by heterozygous pathogenic mutations in two known genes: KDM6A (~20% cases) and KMT2D (~80% cases). Both genes are broadly expressed in many tissues and their activity spans temporally from development to postnatal adult life. KS patients present with various degrees of clinical abnormalities, including severe muscular hypotonia and reduced muscle strength. Whether hypotonia develops as a consequence of nerve conduction malfunction or it is due to a cell-autonomous primary defect in skeletal muscle is currently unknown. Further, skeletal muscle tissue from patients affected by KS has not been thoroughly studied. Our main hypothesis is that skeletal muscle tissue is primarily affected by mutations in KMT2D, which results in dysregulated muscle function. We propose to validate our hypothesis via the following specific Aims: 1) Define primary versus secondary muscle function defects using constitutive and conditional mouse models of KS; 2) Determine the gene networks and molecular targets of KMT2D driving muscle hypotonia in constitutive and conditional KS mouse models; 3) Define muscle satellite cell heterogeneity and `immaturity' in conditional and constitutive KS models, as well as in human patients. The work proposed will fill major gaps in our lack of knowledge about etiology of hypotonia in Kabuki syndrome and will pave the way for clinical improvements of patient care.

项目总结