A5086645638- Muscle Physiology and Disorders
- Cardiomyopathy and Myosin Studies
- RNA modifications and cancer
- Genomics and Rare Diseases
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- Adipose Tissue and Metabolism
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Metabolism and Genetic Disorders
- Mesenchymal stem cell research
- Biochemical and Molecular Research
- Amino Acid Enzymes and Metabolism
- Ubiquitin and proteasome pathways
- Nerve injury and regeneration
- Osteoarthritis Treatment and Mechanisms
- Single-cell and spatial transcriptomics
- Lysosomal Storage Disorders Research
- Genetics, Aging, and Longevity in Model Organisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Microtubule and mitosis dynamics
- Thyroid Disorders and Treatments
- Glycosylation and Glycoproteins Research
Children's National
2013-2025
National Institute of Neurological Disorders and Stroke
2018-2025
National Institutes of Health
2018-2025
National Hospital
2022
George Washington University
2016-2020
Johns Hopkins Medicine
2012-2014
Johns Hopkins University
2012-2014
Following CNS injury, microglial phagocytosis of damaged endogenous tissue is thought to play an important role in recovery and regeneration. Previous work has focused on delineating mechanisms clearance neurons myelin. Little, however, known the underlying axon debris. We have developed a novel microfluidic platform that enables coculture microglia with bundles axons investigate axons. Using this platform, we find degeneration results induction type-1 interferon genes within microglia....
Nerve conduction within the mammalian central nervous system is made efficient by oligodendrocyte‐derived myelin. Historically, thyroid hormones have a well described role in regulating oligodendrocyte differentiation and myelination during development; however, it remains unclear which hormone receptors are required to drive these effects. This question with clinical relevance since nonspecific receptor stimulation can produce deleterious side‐effects. Here we report that GC‐1, thyromimetic...
RNA-seq is widely used for studying gene expression, but commonly sequencing platforms produce short reads that only span up to two exon junctions per read. This makes it difficult accurately determine the composition and phasing of exons within transcripts. Although long-read improves this issue, not amenable precise quantitation, which limits its utility differential expression studies. We isoform combined with a novel analysis approach compare alternative splicing large, repetitive...
MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in have recently been reported small number of patients presenting with phenotype cerebellar ataxia, congenital muscle involvement histologic findings ranging from myopathic dystrophic and pigmentary retinopathy. The proposed underlying mechanism MSTO1-related disease is suggestive impaired secondary loss function Disorders...
The application of allele-specific gene editing tools can expand the therapeutic options for dominant genetic conditions, either via correction or allelic inactivation in situations where haploinsufficiency is tolerated. Here, we used allele-targeted CRISPR-Cas9 guide RNAs (gRNAs) to introduce inactivating frameshifting indels at an SNV
Abstract Age‐related loss of muscle mass and strength is widely attributed to limitation in the capacity resident satellite cells perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails we damage lose substantial amounts course our normal daily activities. Second, suggests mechanisms repair are some way exhausted, thus limiting regeneration. A third potential option aged environment becomes inimical conduct...
Background: Molecular diagnostics in the genetic myopathies often requires testing of largest and most complex transcript units human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs long turnaround times. Exome sequencin g begun to supplant targeted genes, but there are concerns regarding coverage needed depth very large that frequently cause myopathies. Objective: To evaluate efficiency next-generation technologies provide...
Fibro/adipogenic progenitors (FAPs) are skeletal muscle stromal cells that support regeneration of injured myofibers and their maintenance in healthy muscles. FAPs related to mesenchymal stem (MSCs/MeSCs) found other adult tissues, but there is poor understanding the extent similarity between these cells. Using single-cell RNA sequencing (scRNA-seq) datasets from multiple mouse we have performed comparative transcriptomic analysis. This identified remarkable transcriptional MeSCs, confirmed...
Abstract The urea cycle protects the central nervous system from ammonia toxicity by converting to urea. N-acetylglutamate synthase (NAGS) catalyzes formation of N-acetylglutamate, an essential allosteric activator carbamylphosphate synthetase 1. Enzymatic activity mammalian NAGS doubles in presence L-arginine, but physiological significance activation L-arginine has been unknown. knockout ( Nags −/− ) mouse is animal model inducible hyperammonemia, which develops hyperammonemia without...
To define the transcriptomic changes responsible for histologic alterations in skeletal muscle and their progression collagen VI-related muscular dystrophy (COL6-RD).COL6-RD patient biopsies were stratified into three groups based on overall level of pathologic severity considering degrees fibrosis, fiber atrophy, fatty replacement tissue. Using microarray RNA-Seq, we then performed global gene expression profiling same compared transcriptome with age- sex-matched controls.COL6-RD biopsy...
The application of allele-specific gene editing tools can expand the therapeutic options for dominant genetic conditions, either via correction or allelic inactivation in situations where haploinsufficiency is tolerated. Here, we used allele-targeted CRISPR/Cas9 guide RNAs (gRNAs) to introduce inactivating frameshifting indels at a single nucleotide variant
Biallelic pathogenic variants in the genes encoding dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- C-mannosylation, are rare causes of congenital disorders glycosylation. Pathogenic DPM1 DPM2 associated with muscle-eye-brain (MEB) disease, whereas DPM3 have mostly been reported patients isolated muscle disease-dystroglycanopathy. Thus far, only one affected individual compound heterozygous presenting...
Abstract Background Long-read RNA sequencing, such as Pacific Biosciences’ Iso-Seq method, enables generation of sequencing reads that are 10 kilobases or even longer. These ideal for discovering splice junctions and resolving full-length gene transcripts without time-consuming error-prone techniques transcript assembly junction inference. Results Browser is a Web-based visual analytics tool long-read data produced by isoform (Iso-Seq) techniques. Key features the are: 1) an exon-only...
ABSTRACT RNA-seq is widely used for studying gene expression, but commonly sequencing platforms produce short reads that only span up to two exon-junctions per read. This makes it difficult accurately determine the composition and phasing of exons within transcripts. Although long-read improves this issue, not amenable precise quantitation, which limits its utility differential expression studies. We isoform combined with a novel analysis approach compare alternative splicing large,...
Abstract Biallelic pathogenic variants in the gene encoding nebulin ( NEB ) are a known cause of congenital myopathy. We present two individuals with myopathy and compound heterozygous (NM_001271208.2: c.2079C>A; p.(Cys693Ter) c.21522+3A>G) NEB. Transcriptomic sequencing on patient muscle revealed that extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing to be mutually exclusive 143, these differentially expressed during development adult...
Absence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys DMD, the common mouse model DMD (B10-mdx) does not manifest deficits until late adulthood. This has limited our understanding mechanism and therapeutic approaches to target pediatric onset pathology DMD. Here we show that mdx on DBA/2J genetic background (D2-mdx) displays juvenile-onset degeneration. Molecular histological analysis revealed damage this is linked increased...
Abstract The urea cycle protects the central nervous system from ammonia toxicity by converting to non-toxic urea. N-acetylglutamate synthase (NAGS) is an enzyme that catalyzes formation of (NAG), allosteric activator carbamylphosphate synthetase 1 (CPS1), rate limiting cycle. Enzymatic activity mammalian NAGS doubles in presence L-arginine but physiological significance activation unknown. Previously, we have described creation a knockout ( Nags −/− ) mouse, which develops hyperammonemia...
Fibro/adipogenic progenitors (FAPs) are skeletal muscle stromal cells that support regeneration of injured myofibers and their maintenance in healthy muscles. FAPs related to mesenchymal stem (MeSCs) found other adult tissues, but there is poor understanding the extent similarity between these cells. Using single cell RNA sequencing (scRNA-seq) datasets from multiple mouse tissues we have performed comparative transcriptomic analysis This identified remarkable transcriptional MeSCs confirmed...