A5040466865- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Cardiovascular Effects of Exercise
- MicroRNA in disease regulation
- Cardiac Arrhythmias and Treatments
- Calcium signaling and nucleotide metabolism
- Neuroinflammation and Neurodegeneration Mechanisms
- Lysosomal Storage Disorders Research
- RNA and protein synthesis mechanisms
- Circular RNAs in diseases
- Cancer-related molecular mechanisms research
- Alzheimer's disease research and treatments
- Adenosine and Purinergic Signaling
- Angiogenesis and VEGF in Cancer
- Cancer Diagnosis and Treatment
- Muscle Physiology and Disorders
- Barrier Structure and Function Studies
- Advanced biosensing and bioanalysis techniques
- Genomics, phytochemicals, and oxidative stress
- Nicotinic Acetylcholine Receptors Study
- S100 Proteins and Annexins
- Metabolism, Diabetes, and Cancer
- Mitochondrial Function and Pathology
- Trypanosoma species research and implications
- Nitric Oxide and Endothelin Effects
Columbia University
2009-2025
Columbia University Irving Medical Center
2015-2022
University of California San Francisco Medical Center
2011
The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and also present brain. Mutations RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated mutations result “leaky” channels due decreased binding of calstabin2 (FKBP12.6) subunit, which stabilizes closed state channel. We found that mice heterozygous R2474S mutation Ryr2 (Ryr2-R2474S mice)...
Defective regulation of the cardiac ryanodine receptor (RyR2)/calcium release channel, required for excitation-contraction coupling in heart, has been linked to arrhythmias and heart failure. For example, diastolic calcium “leak” via RyR2 channels sarcoplasmic reticulum identified as an important factor contributing impaired contractility failure ventricular that cause sudden death. In patients with failure, chronic activation “fight or flight” stress response leads protein kinase A (PKA)...
Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor/calcium release channel (RyR2) is thought to play a role in heart failure (HF) progression. Inhibition of this an emerging therapeutic strategy. To explore chronic PKA phosphorylation RyR2 HF pathogenesis and treatment, we generated knockin mouse with aspartic acid replacing serine 2808 (mice are referred herein as RyR2-S2808D+/+ mice). This mutation mimics constitutive hyperphosphorylation RyR2, which causes...
Rationale: Atrial fibrillation (AF) is the most common cardiac arrhythmia, however mechanism(s) causing AF remain poorly understood and therapy suboptimal. The ryanodine receptor (RyR2) major calcium (Ca 2+ ) release channel on sarcoplasmic reticulum (SR) required for excitation-contraction coupling in muscle. Objective: In present study, we sought to determine whether intracellular diastolic SR Ca leak via RyR2 plays a role triggering inhibiting this can prevent AF. Methods Results: We...
Drugs currently approved to coat stents used in percutaneous coronary interventions do not discriminate between proliferating vascular smooth muscle cells (VSMCs) and endothelial (ECs). This lack of discrimination delays reendothelialization healing, increasing the risk late thrombosis following angioplasty. We developed a microRNA-based (miRNA-based) approach inhibit proliferative VSMCs, thus preventing restenosis, while selectively promoting preserving EC function. an adenoviral (Ad)...
Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca2+ leak via the mutant RyR2 channels during diastole. We present atomic models human wild-type (WT) and RyR2-R2474S determined by cryo–electron microscopy with overall resolutions in range 2.6 3.6 Å, reaching local 2.25 unprecedented for channels....
Significance In this study, we demonstrate that type 1 inositol 1,4,5-trisphosphate receptor channels are critically involved in the activation of calcineurin/nuclear factor activated T cells (NFAT)/endothelial nitric oxide synthase signaling pathway endothelial cells. This plays an essential role maintenance normal blood pressure, with important implications clinical scenario.
Rationale: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal arrhythmias young individuals during β-adrenergic stimulation. Objective: This study sought determine effects of a novel RyR2-G230C mutation and whether this RyR2-P2328S alter sensitivity channel luminal calcium (Ca 2+ ). Methods Results: Functional characterizations recombinant human channels were...
Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on sarcoplasmic reticulum (SR) plays major role. To dissect mechanistic...
S100A1, a small homodimeric EF-hand Ca
RyR1-related myopathies (RyR1-RMs) include a wide range of genetic disorders that result from mutations in the RYR1 gene. Pathogenic variants lead to defective intracellular calcium homeostasis and muscle dysfunction. Fixing leaks by stabilizing RyR1 channel has been identified as promising therapeutic target. Gene therapy via prime editing also holds great promise it can cure diseases correcting mutations. However, more than 700 have gene, universal treatment would be suitable solution for...
Abstract The type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca 2+ ) release channel on the sarcoplasmic/endoplasmic reticulum that required for skeletal muscle contraction. RyR1 activity modulated by ligands, including activators Ca and ATP. Patients with inherited mutations in may exhibit weakness as part of a heterogeneous, complex disorder known RYR1 -related myopathy ( -RM) or more recently termed RYR1-related disorders (RYR1-RD). Guided high-resolution structures RyR1,...