Document text
Principal Investigator: Michael Kyba
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $435,293
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Abstract
FSHD affects over 25,000 individuals in the United States. It is the third most common muscular dystrophy by
incidence but may be the most common by prevalence (Orphanet, 2008). The DNA lesion associated with this
disease is a contraction within a series of 3.3 kb repeats (D4Z4 repeats) near the telomere of 4q. The
contraction modifies the chromatin configuration of 4q35.2 which results in misexpression of a gene encoded
within each D4Z4 repeat, DUX4. We have shown that DUX4 is cytotoxic when expressed at high levels in
various cellular model systems, and interferes with myogenic gene expression when expressed at low levels in
satellite cells and myoblasts, and have generated an animal model that recapitulates one key aspect of the
human disease: muscle deterioration in the presence of barely-detectable DUX4 protein. However
mechanistically, DUX4 is still not well understood, we do not have a clear picture of which cell types in muscle
express DUX4 and what the consequence of that expression is, a pathological mechanism explaining muscle
loss still eludes the field, and we suffer from a dearth of specific therapies for FSHD. The research proposed in
this application addresses these issues by (1) probing the mechanism of DUX4-mediated transcription,
including studying inhibitors of that transcription (2) investigating the effects of inhibiting the p300 pathway
genetically and pharmacologically in the mouse model, and (3) studying DUX4 expression in primary cells from
FSHD patients. This research will address key outstanding questions in FSHD, will advance a mechanistic
understanding of DUX4 in FSHD at the molecular, cellular, and tissue levels, and may lead to new therapeutic
directions.
Terms: <4q35><Address><Affect><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Basal Transcription Factor><Basal transcription factor genes><Biologic Models><Biological Models><Biopsy><Blood capillaries><Body Tissues><Cell Body><Cell Fraction><Cell model><Cells><Cellular model><Cessation of life><Chromatin><Chronic><Confusion><Confusional State><Cytology and Pathology><Cytopathology><D4Z4><DNA Binding><DNA Binding Interaction><DNA bound><DNA lesion><Data><Death><Deposit><Deposition><Disease><Disorder><Dose><Drop-seq><E1A Binding Protein p300><EP300><EP300 gene><Embryonic Muscle Cells><Expression Signature><FSHD><Facioscapulohumeral Atrophy><Facioscapulohumeral Muscular Dystrophy><Facioscapulohumeral Type Progressive Muscular Dystrophy><Failure><Fasioscapulohumeral Muscular Dystrophy><Fats><Fatty acid glycerol esters><Fiber><Fibrosis><Gene Down-Regulation><Gene Expression><Gene Expression Profile><Gene Transcription><Gene set enrichment analysis><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Diseases><Genetic Transcription><Genomics><Histone Acetylase><Histone H3><Homeo Domain><Human><Immune><Immunes><Incidence><Individual><Inflammation><KAT3B><Landouzy Dejerine muscular dystrophy><Landouzy-Dejerine Dystrophy><Measures><Mediating><Mental Confusion><Mice><Mice Mammals><Model System><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mononuclear><Murine><Mus><Muscle><Muscle Atrophy><Muscle Disease><Muscle Disorders><Muscle Tissue><Muscle satellite cell><Muscular Atrophy><Muscular Diseases><Muscular Dystrophies><Myoblasts><Myodystrophica><Myodystrophy><Myopathic Conditions><Myopathic Diseases and Syndromes><Myopathic disease or syndrome><Myopathy><Names><Natural regeneration><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Population><Precursor Muscle Cells><Prevalence><Progenitor Cells><Proteins><RNA Expression><Regeneration><Research><Research Resources><Resources><Role><Series><Severity of illness><Skeletal Muscle><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Transcription><Transcription Activation><Transcription Factor Proto-Oncogene><Transcription Repression><Transcription factor genes><Transcriptional Activation><Transcriptional Repression><United States><Voluntary Muscle><Work><capillary><cell type><conformation><conformational><conformational state><conformationally><conformations><cytotoxic><density><disease severity><droplet sequencing><gene expression pattern><gene expression signature><gene repression><genetic condition><genetic disorder><histone acetyltransferase><histone acetyltransferase p300><homeodomain><human disease><human model><improved><in vivo><inhibitor><insight><model of animal><model of human><mouse model><murine model><muscle breakdown><muscle degradation><muscle deterioration><muscle dystrophy><muscle loss><muscle wasting><muscular><muscular disorder><name><named><naming><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><p300><pathway><pharmacologic><progenitor><regenerate><regeneration potential><regenerative potential><satellite cell><social role><stem cells><telomere><transcription factor><transcriptional profile><transcriptional signature>