A5038557249- Cardiomyopathy and Myosin Studies
- Transplantation: Methods and Outcomes
- Cardiovascular Effects of Exercise
- Muscle Physiology and Disorders
- Mechanical Circulatory Support Devices
- Signaling Pathways in Disease
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Cellular Mechanics and Interactions
- Cardiac Structural Anomalies and Repair
- Protein Kinase Regulation and GTPase Signaling
- Organ Transplantation Techniques and Outcomes
- Cardiac Fibrosis and Remodeling
- Renal Diseases and Glomerulopathies
- Cardiovascular Function and Risk Factors
- Cell Adhesion Molecules Research
- Renal Transplantation Outcomes and Treatments
- Caveolin-1 and cellular processes
- Parathyroid Disorders and Treatments
- Aortic aneurysm repair treatments
- Genetic and Kidney Cyst Diseases
- Receptor Mechanisms and Signaling
- Pulmonary Hypertension Research and Treatments
- Aortic Disease and Treatment Approaches
- Genetic Syndromes and Imprinting
The University of Texas Southwestern Medical Center
2015-2025
VA North Texas Health Care System
2021-2025
Cancer Research And Biostatistics
2024
Southwestern Medical Center
2013-2022
Center for Clinical Research (United States)
2022
UCLA Health
2017-2021
Ronald Reagan UCLA Medical Center
2018
Metropolitan College of New York
2015
University of Miami
2005-2014
University of Pennsylvania
2007-2011
Objectives Neuregulin 1 signaling plays an important role in cardiac trabecular development, and sustaining functional integrity adult hearts. Treatment with neuregulin enhances cardiomyocyte differentiation, survival and/or function vitro vivo. It has also been suggested that recombinant 1β1 (NRG1β1) induces proliferation normal injured Here we further explore the impact of on cell cycle activity. Methods Results Adult mice were subjected to 9 consecutive daily injections NRG1β1 or vehicle,...
In beating hearts, phosphorylation of myosin regulatory light chain (RLC) at a single site to 0.45 mol phosphate/mol by cardiac kinase (cMLCK) increases Ca2+ sensitivity myofilament contraction necessary for normal performance. Reduction RLC in conditional cMLCK knock-out mice caused dilation and loss performance 1 week, as shown increased left ventricular internal diameter end-diastole decreased fractional shortening. Decreased conventional or gene ablation did not affect troponin-I...
The well-known, muscle-specific smooth muscle myosin light chain kinase (MLCK) (smMLCK) and skeletal MLCK (skMLCK) are dedicated protein kinases regulated by an autoregulatory segment C terminus of the catalytic core that blocks regulatory (RLC) binding phosphorylation in absence Ca(2+)/calmodulin (CaM). Although it is known a more recently discovered cardiac (cMLCK) necessary for normal RLC vivo physiological performance, information on cMLCK biochemical properties limited. We find fourth...
Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), UGT1A1 (rs5839491) on dolutegravir PK was examined.
Soluble, circulating Klotho (sKlotho) is essential for normal health and renal function. sKlotho shed from the distal convoluted tubule (DCT), its primary source, via enzymatic cleavage. However, physiologic mechanisms that control production, trafficking, shedding are not fully defined. We previously found G protein‐coupled calcium‐sensing receptor (CaSR) co‐localizes with membrane‐bound αKlotho disintegrin/metalloprotease ADAM10 in DCT controls response to CaSR ligands pHo by activating...
To study the functional consequences of various cardiomyopathic mutations in human cardiac alpha-tropomyosin (Tm), a method depletion/reconstitution native Tm and troponin (Tn) complex (Tm-Tn) myofibril preparations has been developed. The endogenous Tm-Tn was selectively removed from myofibrils replaced with recombinant wild-type or mutant proteins. Successful depletion reconstitution steps were verified by SDS-gel electrophoresis loss regain Ca2+-dependent regulation ATPase activity. Five...
The physiological importance of cardiac myosin regulatory light chain (RLC) phosphorylation by its dedicated kinase (cMLCK) has been established in both humans and mice. Constitutive RLC-phosphorylation, regulated the balanced activities cMLCK phosphatase (MLCP), is fundamental to biochemical properties myofilaments. However, limited information available on MLCP. In this study, we hypothesized that striated muscle-specific MLCP subunit, MYPT2, targets catalytic subunit myosin, contributing...
The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging homozygous knock-in mice expressing the cTnI-R21C shows that they develop hypertrophy after 12 months age have abnormal diastolic function is characterized longer filling times impaired relaxation. Electrocardiographic analyses show older elevated heart rates reduced cardiovagal tone. Cardiac myocytes...
Background FSGS is a pattern of podocyte injury that leads to loss glomerular function. Podocytes support other podocytes and capillary structure, oppose hemodynamic forces, form the slit diaphragm, have mechanical properties permit these functions. However, biophysical characteristics glomeruli in disease remain unclear.Methods Using microindentation, atomic force microscopy, immunofluorescence quantitative RT-PCR, three-dimensional collagen gel contraction assay, we studied structural...
Dysfunction of the right ventricle (RV) is closely related to prognosis for patients with RV failure. Therefore, strategies improve failing function are significant. In a mouse failure model, we previously reported that α 1 -adrenergic receptor (α -AR) inotropic responses increased. The present study determined roles both predominant cardiac -AR subtypes A and B) in upregulated inotropy RV. We used model bleomycin-induced pulmonary fibrosis, hypertension, assessed myocardial contractile...
Zipper-interacting protein kinase (ZIPK) is a member of the death-associated family associated with apoptosis in nonmuscle cells where it phosphorylates myosin regulatory light chain (RLC) to promote membrane blebbing. ZIPK mRNA and are abundant heart tissue isolated ventricular neonatal rat cardiac myocytes. An unbiased substrate search performed purified on homogenates led discovery prominent 20-kDa identified as RLC myosin. Biochemical analyses showed phosphorylated at Ser-15 V(max) value...
Smooth muscle contraction initiated by myosin regulatory light chain (RLC) phosphorylation is dependent on the relative activities of Ca(2+)-calmodulin-dependent kinase (MLCK) and phosphatase (MLCP). We have investigated physiological role MLCP subunit MYPT1 in bladder smooth containing a muscle-specific deletion adult mice. Deep-sequencing analyses mRNA immunoblotting revealed that depletion reduced amount PP1cδ with no compensatory changes expression other family members. Phosphatase...
The kidney is the source of sKlotho and kidney-specific loss Klotho leads to a phenotype resembling premature multiorgan failure in Klotho-hypomorphic mice ( kl/kl mice). Ca-sensing receptor (CaSR) are highly expressed distal convoluted tubule (DCT). physiologic mechanisms that regulate levels unknown.
Top-down mass spectrometry (MS) has emerged as a powerful complement to peptide-based proteomics. Despite advancements, the field had limited application clinical proteomics investigations due complexity and poor dynamic range of chromatography used separate intact proteins from tissue biofluids. To address these limitations, we developed two-dimensional (2D) platform that includes isoelectric focusing (IEF) through immobilized pH gradient superficially porous liquid (SPLC). Analysis...
Key points The extent of myosin regulatory light chain phosphorylation (RLC) necessary for smooth muscle contraction depends on the respective activities Ca 2+ /calmodulin‐dependent kinase and phosphatase (MLCP), which contains a subunit MYPT1 bound to catalytic myosin. showed significant constitutive T696 T853 phosphorylation, is predicted inhibit MLCP activity in isolated ileal tissues, with additional upon pharmacological treatment muscarinic agonist carbachol. Electrical field...
Significance Point mutations in the ACTA2 gene encoding smooth muscle (SM) α-actin cause familial thoracic aortic aneurysms and dissections predispose to premature coronary artery disease, stroke, moyamoya disease. Studies on mechanistic basis of these diseases are partly hampered by inability collect affected tissues from living patients. Fibroblasts cultured minimally invasive patient skin biopsies allowed study ACTA2– R258C mutation-induced derangement cell growth interrogation...
Smooth muscle myosin regulatory light chain (RLC) is phosphorylated by Ca2+ /calmodulin-dependent kinase and dephosphorylated phosphatase (MLCP). Tracheal smooth contains significant amounts of binding subunit 85 (MBS85), another targeting (MYPT) family member, in addition to MLCP MYPT1. Concentration/temporal responses carbachol demonstrated similar sensitivities for bovine tracheal force development phosphorylation RLC, MYPT1, MBS85 paxillin. Electrical field stimulation releases ACh from...
The potential alterations to structure and associations with thin filament proteins caused by the dilated cardiomyopathy (DCM) associated tropomyosin (Tm) mutants E40K E54K, hypertrophic (HCM) Tm E62Q L185R, were investigated. In order ascertain what cause of known functional effects may be, structural protein-protein interaction studies conducted utilizing actomyosin ATPase activity measurements spectroscopy. measurements, both HCM DCM mutant E54K increases in Ca2+-induced maximal...
Cytoskeletal structure and its regulation are essential for maintenance of the differentiated state specific types cells their adaptation to physiologic pathophysiologic conditions. Renal glomerular capillaries, composed podocytes, endothelial cells, basement membrane, have distinct structural biophysical properties site injury in many diseases. Calcineurin inhibitors, immunosuppressant drugs used organ transplantation auto-immune diseases, can protect podocytes capillaries from by...
Activation of ErbB2/4 receptor tyrosine kinases in cardiomyocytes by neuregulin treatment is associated with improvement cardiac function, supporting its use human patients heart failure despite the lack a specific mechanism. Neuregulin infusion rodents increases myosin light chain kinase (cMLCK) expression and regulatory (RLC) phosphorylation which may improve actin-myosin interactions for contraction. We generated cMLCK knockout mouse to test hypothesis that necessary neuregulin-induced...