A5048162854- Cardiomyopathy and Myosin Studies
- Protein Kinase Regulation and GTPase Signaling
- Mitochondrial Function and Pathology
- Pluripotent Stem Cells Research
- Congenital heart defects research
- Receptor Mechanisms and Signaling
- Adipose Tissue and Metabolism
- Cardiac Structural Anomalies and Repair
- HER2/EGFR in Cancer Research
- Cardiac Fibrosis and Remodeling
- ATP Synthase and ATPases Research
- Cellular transport and secretion
- Pancreatic function and diabetes
- Transgenic Plants and Applications
- Trypanosoma species research and implications
- Insect and Pesticide Research
- Neuroscience and Neural Engineering
- Toxin Mechanisms and Immunotoxins
- Caveolin-1 and cellular processes
- Genetics, Aging, and Longevity in Model Organisms
- Cardiovascular Function and Risk Factors
- Protein purification and stability
- Circular RNAs in diseases
- Congenital Heart Disease Studies
- Neuroblastoma Research and Treatments
Cardiovascular Institute of the South
2015-2021
Stanford University
2014-2021
Cedars-Sinai Medical Center
2017
Jungheinrich (Germany)
2014-2016
Lucile Packard Children's Hospital
2016
University of California, Los Angeles
2011-2014
The University of Texas Southwestern Medical Center
2005-2009
Max Planck Society
1993
Phosphotyrosine-containing synthetic peptides were used to identify the binding sites for cellular polypeptides involved in nerve growth factor receptor/Trk-mediated signal transduction. In vitro association of SHC and p85 subunit phosphatidylinositol 3'-kinase with Trk tyrosine kinase was prevented only by phosphorylated Y-490- Y-751-containing peptides, respectively. spite close proximity site that phospholipase C gamma (Y-785), both target proteins are able interact same receptor molecule...
Drug Affinity Responsive Target Stability is a general methodology for identifying and studying protein-ligand interactions. The technique based on the principle that when small molecule compound binds to protein, interaction stabilizes target protein's structure such it becomes protease resistant. DARTS particularly useful initial identification of protein targets molecules, but can also be used validate potential interactions predicted or identified by other means estimate affinity...
The ability to differentiate human pluripotent stem cells (hPSCs) into cardiomyocytes (CMs) makes them an attractive source for repairing injured myocardium, disease modeling, and drug testing. Although current differentiation protocols yield hPSC-CMs >90% efficiency, exhibit immature characteristics. With the goal of overcoming this limitation, we tested effects varying passive stretch on engineered heart muscle (EHM) structural functional maturation, guided by computational modeling. Human...
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.
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...
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...
Phosphatidylinositol 4-kinases play essential roles in cell signaling and membrane trafficking. They are divided into type II III families, which have distinct structural enzymatic properties essentially unrelated sequence. Mammalian cells express two isoforms, phosphatidylinositol 4-kinase IIα (PI4KIIα) IIβ (PI4KIIβ). Nearly all of PI4KIIα, about half PI4KIIβ, associates integrally with membranes, requiring detergent for solubilization. This tight association is because palmitoylation a...
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...
Myosin 1C, the first mammalian single-headed myosin to be purified, cloned, and sequenced, has been implicated in translocation of plasma membrane channels transporters. Like other forms I (of which eight exist humans) 1C consists motor, neck, tail domains. The neck domain binds calmodulins more tightly absence than presence Ca(2+). Release exposes binding sites for anionic lipids, particularly phosphoinositides. domain, an isoelectic point 10.5, interacts with lipid headgroups. When both...
Mammalian cells contain two isoforms of the type II PI4K (phosphoinositol 4-kinase), PI4KIIα and β. These 55 kDa proteins have highly diverse N-terminal regions (approximately residues 1–90) but conserved catalytic domains from residue 91 to C-termini). Nearly entire pool behaves as an integral membrane protein, in spite a lack transmembrane domain. This association with membranes is due palmitoylation cysteine-rich motif, CCPCC, located within Although CCPCC motif PI4KIIβ, only 50% PI4KIIβ...
Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, associated with over 1000 mutations, many in β-cardiac myosin (MYH7). Molecular studies different HCM mutations have revealed a diversity effects on ATPase and load-sensitive rate detachment from actin. It has been difficult to predict how such diverse molecular combine influence forces at cellular level further phenotypes. This study focused P710R mutation that dramatically decreased vitro...
hiPSC-CMs are a novel model system for cardiovascular diseases, with proven utility in cardiac channelopathies, however, how accurately recapitulate the signaling pathways regulating contractility and remodeling of adult cardiomyocytes remains to be determined. As ß-ARs key regulators both remodeling, we examined ß-AR at different stages hiPSC-CM maturation. hiPSCs, derived from healthy controls, were studied 0, 14, 30, 60d after induction under isoproterenol (ISO) stimulation ± ß1 or ß2...
Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and has a unique phenotype with characteristically extensive hypertrabeculation of left ventricle, similar to embryonic suggesting developmental defect myocardium. However, studying this disease been challenging due lack an animal model that can faithfully recapitulate clinical LVNC. To address this, we showed patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)...
Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and has a unique phenotype with characteristically extensive hypertrabeculation of left ventricle, similar to embryonic suggesting developmental defect myocardium. However, in-depth investigation this disease been challenging due lack animal models that can faithfully recapitulate clinical LVNC. In study, we demonstrated patient-specific induced pluripotent stem cell-derived cardiomyocytes...
Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission fragmentation are result of pathologic stresses such as ischemia, an indicator poor health, lead to mitophagy However, recent studies demonstrate inhibiting also results cardiac impairment, suggesting is important maintaining normal function. In this study, we identify novel physiological adaptation increased demand. Using two...
In cardiomyocytes (CMs), mitochondria play a dual role, maintaining the high energy supply required for rhythmic contraction, but also regulating critical cell death signaling. Impaired mitochondrial function can affect cellular homeostasis and contribute to sub-lethal injury; if impairment is more severe or persistent, pro-death pathways are activated. It becoming increasingly clear, however, that within population of cells there considerable heterogeneity in between individual CMs; single...