A5023886416- Muscle Physiology and Disorders
- Mesenchymal stem cell research
- RNA Research and Splicing
- Tissue Engineering and Regenerative Medicine
- Pluripotent Stem Cells Research
- Osteoarthritis Treatment and Mechanisms
- Cardiomyopathy and Myosin Studies
- Periodontal Regeneration and Treatments
- Neurogenetic and Muscular Disorders Research
- CRISPR and Genetic Engineering
- Adipose Tissue and Metabolism
- Telomeres, Telomerase, and Senescence
- Animal Genetics and Reproduction
- Electrospun Nanofibers in Biomedical Applications
- Peptidase Inhibition and Analysis
- Veterinary Oncology Research
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Monoclonal and Polyclonal Antibodies Research
- Congenital heart defects research
- Genetic Neurodegenerative Diseases
- Protease and Inhibitor Mechanisms
- Genomics and Chromatin Dynamics
- Bone health and osteoporosis research
Minneapolis Heart Institute Foundation
2016-2025
University of Minnesota
2016-2025
Goce Delcev University
2011-2021
University of Minnesota Medical Center
2020
The University of Texas Southwestern Medical Center
2006-2009
University "St. Kliment Ohridski" - Bitola
2009
Southwestern Medical Center
2008
Hokkaido University
2003-2006
Kumamoto University
2004
White adipose (fat) tissues regulate metabolism, reproduction, and life span. Adipocytes form throughout life, with the most marked expansion of lineage occurring during postnatal period. develop in coordination vasculature, but identity location white adipocyte progenitor cells vivo are unknown. We used genetically mice to isolate proliferating renewing adipogenic progenitors. found that adipocytes descend from a pool these progenitors already committed, either prenatally or early life....
Abstract Bone marrow mesenchymal stem cells (MSCs) are candidate for cartilage tissue engineering. This is due to their ability undergo chondrogenic differentiation after extensive expansion in vitro and stimulation with various biomaterials three‐dimensional (3‐D) systems. Collagen type II one of the major components hyaline plays a key role maintaining chondrocyte function. study aimed at analyzing MSC response during culture different types extracellular matrix (ECM) focus on influence...
Ectopic expression of the double homeodomain transcription factor DUX4 causes facioscapulohumeral muscular dystrophy (FSHD). Mechanisms action are currently unknown. Using immortalized human myoblasts with a titratable transgene, we identify by mass spectrometry an interaction between C-terminus and histone acetyltransferases p300/CBP. Chromatin immunoprecipitation shows that recruits p300 to its target gene, ZSCAN4, displaces H3 from center binding site, induces H3K27Ac in vicinity, but...
Genetic modification is critically enabling for studies addressing specification and maintenance of cell fate; however, methods engineering modifications are inefficient. We demonstrate a rapid efficient recombination system in which an inducible, floxed cre allele replaces itself with incoming transgene. target this inducible cassette exchange (ICE) to the (HPRT) locus murine embryonic stem cells (ESCs) primary from derivative ICE mice. Using lentivectors, we at randomly integrated human...
Abstract Muscle regeneration occurs through activation of quiescent satellite cells whose progeny proliferate, differentiate, and fuse to make new myofibers. We used a transgenic Pax7-ZsGreen reporter mouse prospectively isolate stem skeletal muscle by flow cytometry. show that Pax7-expressing (satellite cells) in the limb, head, diaphragm muscles are homogeneous size granularity uniformly labeled certain cell surface markers, including CD34 CD29. The frequency varies between types with age....
Abstract Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression the transcription factor DUX4; however, DUX4 expression very low, and protein has not been detected directly in patient biopsies. Efforts to model mice have foundered either being too severe, or lacking muscle phenotypes. Here we show that endogenous facioscapulohumeral dystrophy-specific polyadenylation signal surprisingly inefficient, use this finding develop an...
Highlights•Widespread low-level expression of DUX4 from chrX causes male-specific lethality•Retinal leads to retinal vascular pathology•Low levels impair proliferation and differentiation primary myoblasts•Impaired regeneration by donor satellite cells provides a model for pathologySummaryFacioscapulohumeral muscular dystrophy (FSHD) is an enigmatic disease associated with epigenetic alterations in the subtelomeric heterochromatin D4Z4 macrosatellite repeat. Each repeat unit encodes DUX4,...
Facioscapulohumeral muscular dystrophy (FSHD) results from mutations causing overexpression of the transcription factor, DUX4, which interacts with histone acetyltransferases, EP300 and CBP. We describe activity a new spirocyclic EP300/CBP inhibitor, iP300w, inhibits cytotoxicity DUX4 protein reverses most target genes, in engineered cell lines FSHD myoblasts, as well an animal model. In evaluating effect iP300w on global H3 acetylation, we discovered that leads to dramatic increase total...
Abstract The first step in disease pathogenesis for arboviruses is the establishment of infection following vector transmission. For La Crosse virus (LACV), leading cause pediatric arboviral encephalitis North America, and other orthobunyaviruses, initial course skin not well understood. Using an intradermal (ID) model LACV mice, we find that infects replicates nearly exclusively within skin-associated muscle cells panniculus carnosus (PC) epidermal or dermal like most arbovirus families....
Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic alterations at the D4Z4 macrosatellite repeat locus on chromosome 4, resulting in inappropriate expression of DUX4 protein. The protein therefore primary molecular target for therapeutic intervention. We have developed a high-throughput screen based toxicity when overexpressed C2C12 myoblasts, and identified inhibitors DUX4-induced from within diverse set 44,000 small, drug-like molecules. A total 1,280 hits were then...
Facioscapulohumeral muscular dystrophy (FSHD) is caused by inappropriate expression of the double homeodomain protein DUX4. DUX4 has bimodal effects, inhibiting myogenic differentiation and blocking MyoD at low levels expression, killing myoblasts high levels. Pax3 Pax7, which contain related homeodomains, antagonize cell death phenotype in C2C12 cells, suggesting some type competitive interaction. Here, we show that effects on require homeodomains but do not C-terminal activation domain We...
Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression the DUX4 gene; however, protein rare and difficult to detect in human muscle biopsies, pathological mechanisms are obscure. FSHD also a chronic disease that progresses slowly over decades. We used sporadic, low-level, muscle-specific expression enabled iDUX4pA-HSA mouse develop long-term model. After 6 months extremely low sporadic expression, dystrophic presented hallmarks histopathology, including degeneration,...
Pax3-induced pluripotent stem cell-derived myogenic progenitors display an embryonic molecular signature but become postnatal upon transplantation. Because this correlates with upregulation of Notch signaling, here we probed whether NOTCH1 is required for in vivo maturation by performing gain- and loss-of-function studies inducible Pax3 (iPax3) progenitors. Transplantation revealed that Notch1 signaling did not change the number donor-derived fibers; however, overexpression cohorts showed...
p300 and CBP are paralogous epigenetic regulators promising therapeutic targets for which TPD offers the potential to achieve paralog-selective degradation.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by contractions of D4Z4 repeats at 4q35.2 thought to induce misregulation nearby genes, one which, DUX4, actually localized within each repeat. A conserved ORF (mDUX), embedded D4Z4-like repeats, encoding a double-homeodomain protein, was recently identified on mouse chromosome 10. We show here that high level mDUX expression induces myoblast death, while low non-toxic levels block myogenic differentiation down-regulating MyoD and Myf5....