A5057990811- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Muscle Physiology and Disorders
- Cardiovascular Function and Risk Factors
- Mitochondrial Function and Pathology
- Congenital heart defects research
- RNA Research and Splicing
- Viral Infections and Immunology Research
- Cardiac Structural Anomalies and Repair
- RNA modifications and cancer
- ATP Synthase and ATPases Research
- Advanced MRI Techniques and Applications
- RNA and protein synthesis mechanisms
- Cardiovascular Conditions and Treatments
- Congenital Heart Disease Studies
- Adipose Tissue and Metabolism
- Cellular Mechanics and Interactions
- Cardiac pacing and defibrillation studies
- Cardiac Arrhythmias and Treatments
- Metabolism, Diabetes, and Cancer
- Tissue Engineering and Regenerative Medicine
- Signaling Pathways in Disease
- Cardiac electrophysiology and arrhythmias
- Genetics, Aging, and Longevity in Model Organisms
- Metabolism and Genetic Disorders
University of Washington
2019-2024
Seattle University
2019-2023
Stanford University
2015-2021
Institute of Translational Health Sciences
2021
Cardiovascular Institute of the South
2016-2019
University of California, Davis
2016-2018
Cedars-Sinai Medical Center
2017
Lucile Packard Children's Hospital
2016
Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating structure-function relationships, there still much be learned about mechanisms that link altered cardiac energetics phenotypes. In this work, we test hypothesis changes represent common...
Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission fragmentation are result of pathological stresses, such as ischemia, an indicator poor health, lead to mitophagy However, recent studies demonstrate inhibiting also results decreased function cardiac impairment, suggesting is important maintaining bioenergetic homeostasis.
Abstract Even in healthy aging, cardiac morbidity and mortality increase with age both mice humans. These effects include a decline diastolic function, left ventricular hypertrophy, metabolic substrate shifts, alterations the proteome. Previous work from our laboratory indicated that short‐term (10‐week) treatment rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. In this report, we demonstrate rapamycin‐dependent improvement function is highly persistent, while...
Significance Heart disease is the leading cause of death worldwide, and hypertrophic cardiomyopathy (HCM) most common inherited form heart disease, affecting over 1 in 200 people. Mutations myosin, motor protein responsible for contraction heart, are a HCM but have diverse effects on biomechanics myosin protein. We demonstrate that complex biomechanical mutations associated with can be effectively studied understood using multiscale experimental computational modeling approach. This work...
Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM attributed to mutations β-cardiac myosin, the motor protein powers ventricular contraction. This study reports how two early-onset mutations, D239N and H251N, affect molecular biomechanics human myosin. We observed increases (20%-90%) actin gliding velocity, intrinsic force, ATPase activity comparison wild-type Moreover, for we found significantly lower...
Abstract Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent HCM-causing mutations are found human β-cardiac myosin. Previous studies looking at effect HCM on force, velocity ATPase activity catalytic domain myosin have not shown clear trends leading hypercontractility molecular scale. Here we present functional data showing that four separate located head-tail (R249Q, H251N) head-head (D382Y, R719W) interfaces a...
Human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) are a powerful platform for uncovering disease mechanisms and assessing drugs efficacy/toxicity.However, the accuracy with which hiPSC-CMs recapitulate contractile remodeling signaling of adult is not fully known.We used b-adrenergic receptor (b-AR) as prototype to determine evolution component expression function during hiPSC-CM maturation.In "early" (less than or equal d 30), b2-ARs primary source cAMP/PKA signaling.With...
Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv activator promising preclinical data that currently clinical trials. While it known danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking.Permeabilized porcine cardiac tissue myofibrils were used for X-ray diffraction mechanical measurements. A mouse model genetic dilated...
The biochemical SRX (super relaxed) state of myosin has been defined as a low ATPase activity state. This can conserve energy when the is not recruited for muscle contraction. correlated with structurally ordered (verses disordered) thick filaments. two states may be linked via common interacting head motif (IHM) where heads heavy meromyosin (HMM), or myosin, fold back onto each other and form additional contacts S2 filament. Experimental observations SRX, IHM, filaments, however, do always...
Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms congenital heart disease, causing progressive right ventricular (RV) dilation failure. Little known the mechanisms underlying this combination preload afterload stressors. We developed murine model PI PS (PI+PS) to identify clinically relevant pathways biomarkers disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated end-diastolic pressures) at 1...
Background: Inhibiting contractility by targeting cardiac myosin is an effective treatment for patients with hypertrophic cardiomyopathy (HCM). Aficamten a second in class inhibitor promising clinical data showing improvements hemodynamics and symptoms HCM. While it known that inhibits force cardiomyocyte stabilizing the weak pre-powerstroke conformation, effects on structure kinetics during loaded contraction are lacking. Methods: Permeabilized porcine tissue myofibrils were used...
Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension-generating capacity. We demonstrated cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts contractile dysfunction. employed a transgenic murine model of caused by the D230N-tropomyosin (Tm) mutation designed sarcomere-based intervention specifically targeting integral D230N-Tm using multiscale computational models...
Sarcomere activation in striated muscle requires both thin filament–based and thick mechanisms. Recent studies have shown that myosin heads on the filaments undergo OFF to ON structural transitions response calcium (Ca2+) permeabilized porcine myocardium presence of a small molecule inhibitor eliminated active force. The changes X-ray diffraction signatures were interpreted as Ca2+ acting activate filaments. Alternatively, binding troponin could initiate Ca2+-dependent crosstalk from...
Background: In patients with complex congenital heart disease, such as those tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload stress, leading RV hypertrophy and eventually failure. The role lipid peroxidation, a potent form oxidative in mediating failure disease unknown. Methods: Lipid peroxidation mitochondrial function structure were assessed myocardium collected from normal systolic (RV fractional area change, 47.3±3.8%) showing decreased 26.6±3.1%). mechanism...
Abstract We sought to establish a large animal model of inherited hypertrophic cardiomyopathy (HCM) with sufficient disease severity and early penetrance for identification novel therapeutic strategies. HCM is the most common cardiac disorder affecting 1 in 250–500 people, yet few therapies its treatment or prevention are available. A research colony purpose-bred cats carrying A31P mutation MYBPC3 was founded using sperm from single heterozygous male cat. Cardiac function four generations...
Precise regulation of sarcomeric contraction is essential for normal cardiac function. The heart must generate sufficient force to pump blood throughout the body, but either inadequate or excessive can lead dysregulation and disease. Myosin regulatory light chain (RLC) a thick-filament protein that binds neck myosin heavy chain. Post-translational phosphorylation RLC (RLC-P) by kinase known influence acto-myosin interactions, thereby increasing production Ca
Abstract Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Detailed mechanism of action these agents can help predict potential unwanted affects and identify patient populations that benefit most from them. Danicamtiv activator promising preclinical data currently clinical trials. While it known danicamtiv increases force cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode are lacking. Using...
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening left ventricle (LV), hypercontractility, and impaired relaxation. HCM caused primarily heritable mutations in sarcomeric proteins, such as β myosin heavy chain. Until recently, medications clinical use for did not directly target underlying contractile changes sarcomere. Here, we investigate novel small molecule, RLC-1, identified bovine cardiac myofibril high-throughput screen. RLC-1 highly...
The timing and magnitude of force generation by a muscle depend on complex interactions in compliant, contractile filament lattice. Perturbations these can result cardiac diseases. In this study, we address the fundamental challenge connecting temporal features twitches to underlying rate constants their perturbations associated with genetic cardiomyopathies. Current state-of-the-art metrics for characterizing mechanical consequence disease do not utilize information embedded complete time...
Abstract Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent HCM-causing mutations are found human β-cardiac myosin. Previous studies looking at effect HCM on force, velocity ATPase activity catalytic domain myosin have not shown clear trends leading hypercontractility molecular scale. Here we present functional data showing that four separate located head-tail (R249Q, H251N) head-head (D382Y, R719W) interfaces a...
Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)- the leading cause heart failure 1,2 . Progress towards developing precision therapeutics for defining underlying determinants DCM has been centric with negligible attention directed fibroblasts despite their role regulating best predictor severity, cardiac fibrosis 3,4 Given that to reverse is a major limitation both standard care...