A5060750733- Muscle Physiology and Disorders
- Cardiomyopathy and Myosin Studies
- Congenital heart defects research
- Cardiovascular Effects of Exercise
- Single-cell and spatial transcriptomics
- Cardiac electrophysiology and arrhythmias
- Pulmonary Hypertension Research and Treatments
- Pluripotent Stem Cells Research
- Cardiovascular Function and Risk Factors
- CRISPR and Genetic Engineering
- Protein Kinase Regulation and GTPase Signaling
- Phosphodiesterase function and regulation
- Hepatitis C virus research
- Heavy Metal Exposure and Toxicity
- Receptor Mechanisms and Signaling
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Virus-based gene therapy research
- Cancer, Hypoxia, and Metabolism
- Cellular Mechanics and Interactions
- Eosinophilic Esophagitis
- Ion channel regulation and function
- Tissue Engineering and Regenerative Medicine
- Trace Elements in Health
- Neuroscience and Neural Engineering
Johns Hopkins University
2017-2025
Johns Hopkins Medicine
2019-2025
Medical College of Wisconsin
2024-2025
Muscular Dystrophy Association
2024
Institute of Cardiology
2022
Loyola University Chicago
2013-2021
University of Baltimore
2021
UNSW Sydney
2019
Johns Hopkins Hospital
2019
South Western Sydney Local Health District
2019
Significance Transient receptor potential canonical 6 (TRPC6) is an important mediator of pathological hypertrophy and fibrosis, contributing to renal cardiac disease. However, no selective TRPC6 inhibitor with in vivo efficacy has been developed tested determine if nongenetic channel suppression ameliorates disease intact animals. We orally bioavailable TRPC6-specific inhibitor, BI 749327, revealing its capacity improve function reduce chamber dilation fibrosis the context abnormal...
Abstract Cardiomyocytes undergo significant structural and functional changes after birth, these fundamental processes are essential for the heart to pump blood growing body. However, due challenges of isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects mature phenotype remains poorly understood. Here we implement large-particle sorting analyze myocytes from neonatal adult hearts. Early exhibit wide-ranging transcriptomic size...
Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits CaMKII inhibition in numerous preclinical models heart disease, translation antagonists into humans has been stymied by low potency, toxicity, an enduring concern for adverse effects on cognition due to established role learning memory. To address these challenges, we asked whether any clinically approved drugs,...
Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (microdystrophins) are underway for Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy this strategy with 4 microdystrophin constructs (3 in clinical a variant largest construct), severe mouse model DMD, using AAV comparable those trials. achieved levels expression striated muscles cardiac approximately 10-fold higher than that observed skeletal muscle....
The immaturity of pluripotent stem cell (PSC)-derived tissues has emerged as a universal problem for their biomedical applications. While efforts have been made to generate adult-like cells from PSCs, direct benchmarking PSC-derived against in vivo development not established. Thus, maturation status is often assessed on an ad-hoc basis. Single RNA-sequencing (scRNA-seq) offers promising solution, though cross-study comparison limited by dataset-specific batch effects. Here, we developed...
Abstract Skeletal muscle can repair and regenerate due to resident stem cells known as satellite cells. The muscular dystrophies are progressive wasting diseases underscored by chronic damage that is continually repaired cell-driven regeneration. Here we generate a genetic strategy mediate cell ablation in dystrophic mouse models investigate how impact disease trajectory. Unexpectedly, observe depletion of reduces features, with improved histopathology, enhanced sarcolemmal stability...
Muscle contraction, which is initiated by Ca2+, results in precise sliding of myosin-based thick and actin-based thin filament contractile proteins. The interactions between myosin actin are finely tuned three isoforms binding protein-C (MyBP-C): slow-skeletal, fast-skeletal, cardiac (ssMyBP-C, fsMyBP-C cMyBP-C, respectively), each with distinct N-terminal regulatory regions. skeletal MyBP-C conditionally coexpressed muscle, but little known about their function. Therefore, to characterize...
Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy dysfunction increases autophagy. oxidation cysteine-42 is also induced these stressors, which blunts its cardioprotective effects.
Heterozygous gain-of-function (GOF) mutations of hypoxia-inducible factor 2α (HIF2A), a key hypoxia-sensing regulator, are associated with erythrocytosis, thrombosis, and vascular complications that account for morbidity mortality patients. We demonstrated the pathology HIF2A GOF is independent erythrocytosis. generated GOF-induced pluripotent stem cells (iPSCs) differentiated them into endothelial (ECs) smooth muscle (SMCs). Unexpectedly, HIF2A-SMCs, but not HIF2A-ECs, were phenotypically...
Cardiovascular disease is the leading cause of mortality in US. Studies suggest a role for environmental exposures etiology cardiovascular disease, including exposure to arsenic through drinking water. Arsenic during pregnancy has been shown have effects on offspring, but few studies examined impacts maternal health. While our prior work documented detrimental effect heart pregnancy, current study examines gestational postpartum. Timed-pregnant wild-type (C57BL/6J) mice were exposed 0, 100...
Neurons regulate cardiomyocyte proliferation through clock genes.
A limitation in the application of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) is failure these cells to achieve full functional maturity. The mechanisms by which directed differentiation differs from endogenous development, leading consequent PSC-CM maturation arrest, remain unclear. Here, we generate a single-cell RNA sequencing (scRNA-seq) reference mouse vivo CM with extensive sampling previously difficult-to-isolate perinatal time periods. We subsequently isogenic embryonic...
Myosin binding protein-C (MyBP-C) exists in three major isoforms: slow skeletal, fast and cardiac. While cardiac MyBP-C (cMyBP-C) expression is restricted to the heart adult, it transiently expressed neonatal stages of some skeletal muscles. However, unclear whether this necessary for proper development function muscle. Our aim was determine absence cMyBP-C alters structure, function, or isoform adult muscle using a null mouse model (cMyBP-C(t/t)). Slow both muscles, whereas mostly...
This meeting report summarizes the presentations and discussions held at summit on Challenges in Gene Therapy hosted by Muscular Dystrophy Association (MDA) 2023. Topics covered include safety issues, mitigation strategies practical considerations pertaining to clinical translation of gene therapies for neuromuscular disease. The listing actionable recommendations will assist overall efforts field achieve safe efficacious disease patients.
Gene mutations causing loss of dystrophin result in the severe muscle disease known as Duchenne muscular dystrophy (DMD). Despite efforts at genetic repair, DMD therapy remains largely palliative. Loss destabilizes sarcolemmal membrane, inducing mechanosensitive cation channels to increase calcium entry and promote cell damage and, eventually, dysfunction. One putative channel is transient receptor potential canonical 6 (TRPC6); we have shown that TRPC6 contributed abnormal force...
The ability to image the entire adult mouse heart at high resolution in 3-D would provide enormous advantages study of disease. However, a technique for imaging nuclear/cellular detail as well overall structure with minimal effort is lacking. To solve this problem, we modified benzyl alcohol:benzyl benzoate (BABB) clearing by labeling hearts periodic acid Schiff (PAS) stain. We then imaged combination two-photon fluorescence microscopy and automated tile-scan imaging/stitching. Utilizing...
Background: The mouse is the most widely used mammal in experimental biology. Although many clinically relevant vivo cardiac stressors are used, one that has eluded translation long-term pacing. Here, we present first method to chronically simulate and simultaneously record electrical activity conscious mobile mice. We then apply it study right ventricular pacing induced electromechanical dyssynchrony its reversal (resynchronization). Methods Results: includes a custom implantable bipolar...
The immaturity of pluripotent stem cell (PSC)-derived tissues has emerged as a universal problem for their biomedical applications. While efforts have been made to generate adult-like cells from PSCs, direct benchmarking PSC-derived against in vivo development not established. Thus, maturation status is often assessed on an ad-hoc basis. Single RNA-sequencing (scRNA-seq) offers promising solution, though cross-study comparison limited by dataset-specific batch effects. Here, we developed...