A5025425176- Mitochondrial Function and Pathology
- Cardiac electrophysiology and arrhythmias
- Signaling Pathways in Disease
- Ion channel regulation and function
- RNA Research and Splicing
- Adipose Tissue and Metabolism
- Cardiomyopathy and Myosin Studies
- ATP Synthase and ATPases Research
- Congenital heart defects research
- RNA modifications and cancer
- Autophagy in Disease and Therapy
- Neuroscience and Neuropharmacology Research
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- Muscle Physiology and Disorders
- Genetic Neurodegenerative Diseases
- Cardiac Fibrosis and Remodeling
- Cardiovascular Function and Risk Factors
- RNA and protein synthesis mechanisms
- Thyroid Disorders and Treatments
- 14-3-3 protein interactions
- Erythrocyte Function and Pathophysiology
- Cardiac Ischemia and Reperfusion
- Ion Transport and Channel Regulation
- MicroRNA in disease regulation
University of Iowa
2015-2024
Fraternal Order of Eagles
2016-2024
Cardiovascular Research Center
2022
Diabetes Research Center
2020
Weatherford College
2015
Institute of Macromolecular Chemistry
2012-2014
The University of Texas Southwestern Medical Center
2006-2014
Lake Chad Basin Commission
2013
Vanderbilt University Medical Center
2005-2008
John F. Kennedy Center for the Performing Arts
2008
Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads pathological cardiac hypertrophy remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated transduction signals heart, but specific isoforms CaMKII that mediate signaling have not fully defined. To investigate potential involvement disease CaMKIIdelta, major isoform expressed we generated CaMKIIdelta-null mice. These mice are viable display no overt...
SummaryObesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the regulates systemic energy homeostasis via MED13, a subunit of Mediator complex, which controls transcription by thyroid hormone other nuclear receptors. in turn, is negatively regulated heart-specific microRNA, miR-208a. Cardiac-specific overexpression MED13 or pharmacologic inhibition miR-208a mice confers resistance to high-fat diet-induced obesity improves insulin...
Obesity and metabolic syndrome are associated with mitochondrial dysfunction deranged regulation of genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional that regulates metabolism biogenesis through stimulation nuclear hormone receptors other transcription factors. We report the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 miR-378*, which counterbalance actions PGC-1β. Mice genetically lacking miR-378* resistant to high-fat diet-induced...
Maintenance of skeletal muscle structure and function requires efficient precise metabolic control. Autophagy plays a key role in homeostasis diverse tissues by recycling cellular constituents, particularly under conditions caloric restriction, thereby normalizing metabolism. Here we show that histone deacetylases (HDACs) 1 2 control autophagy flux mice. Skeletal muscle-specific deletion both HDAC1 HDAC2 results perinatal lethality subset mice, accompanied mitochondrial abnormalities...
Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 cleaved by the calcium ion-dependent protease calpain, which disrupts E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of liberates an N-terminal fragment (JP2NT) translocates to nucleus, binds genomic DNA, controls expression spectrum genes in cardiomyocytes. Transgenic overexpression JP2NT mice...
Abstract Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein‐ lipid‐enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca 2+ , lipid, other metabolites between these organelles. Defective MERCs associated with cellular oxidative stress, neurodegenerative disease, cardiac skeletal muscle pathology via mechanisms poorly understood. We previously demonstrated muscle‐specific knockdown (KD) mitochondrial fusion mediator...
Activation of cellular Ca2+ signaling molecules appears to be a fundamental step in the progression cardiomyopathy and arrhythmias. Myocardial overexpression constitutively active Ca2+-dependent phosphatase calcineurin (CAN) causes severe marked by left ventricular (LV) dysfunction, arrhythmias, increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk death.We found that activity expression second Ca2+-activated molecule,...
Fertilization triggers a rise in intracellular Ca 2+ concentration ([Ca ] i ) the egg that initiates series of events known as activation. These include cortical granule exocytosis establishes block to polyspermy, resumption meiosis, and recruitment maternal mRNAs into polysomes for translation. Several calcium-dependent proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), have been implicated However, precise role CaMKII mediating specific activation identity...
Abstract The heart requires a continuous supply of energy but has little capacity for storage and thus relies on exogenous metabolic sources. We previously showed that cardiac MED 13 modulates systemic homeostasis in mice. Here, we sought to define the extra‐cardiac tissue(s) respond signaling. show overexpression transgenic ( 13cTg) mice confers lean phenotype is associated with increased lipid uptake, beta‐oxidation mitochondrial content white adipose tissue WAT ) liver. Cardiac expression...
Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate differentiation, growth metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 ( Lrrc8a ) functionally encodes a swell-activated anion channel regulates PI3K-AKT, ERK1/2, mTOR signaling, myoblast fusion, cellular oxygen consumption, glycolysis cells. LRRC8A over-expression KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels fully...
The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure, flow. endothelial volume-regulated anion channel (VRAC) has been proposed be mechanosensitive thereby sense fluid flow hydrostatic pressure regulate function. Here, we show that the leucine-rich repeat-containing protein 8a, LRRC8A (SWELL1), is required for VRAC human umbilical vein cells (HUVECs). Endothelial regulates AKT-endothelial nitric oxide synthase (eNOS) signaling under...
Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates the β2a subunit of voltage-gated Ca2+ channels at Thr498 to facilitate cardiac L-type channels. CaMKII colocalizes with in cardiomyocytes and also binds a domain that contains exhibits an amino acid sequence similarity autoinhibitory binding NMDA receptor NR2B (Grueter, C. E. et al. (2006) Mol. Cell 23, 641). Here, we explore selectivity actions among channel β isoforms. β1b, β2a, β3, β4 isoforms similar initial rates final...
Members of the calmodulin-binding transcription activator (CAMTA) family proteins function as calcium-sensitive regulators gene expression in multicellular organisms ranging from plants to humans. Here, we show that global or nervous system deletion CAMTA1 mice causes severe ataxia with Purkinje cell degeneration and cerebellar atrophy, partially resembling consequences haploinsufficiency human locus. Gene-expression analysis identified a large collection neuronal genes were dysregulated...
Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 ULK2 thought to play primarily redundant roles initiation, but whether their function is developmentally determined, potentially having an impact on integrity unknown. Here, we demonstrate that perinatal loss or...
Transcriptional remodeling is known to contribute heart failure (HF). Targeting stress-dependent gene expression mechanisms may represent a clinically relevant therapy option. We recently uncovered salutary mechanism in the whereby JP2 (junctophilin-2), an essential component of excitation-contraction coupling apparatus, site-specifically cleaved and releases N-terminal fragment (JP2NT [N-terminal JP2]) that translocates into nucleus functions as transcriptional repressor HF-related genes....
The mediator complex, a multisubunit nuclear plays an integral role in regulating gene expression by acting as bridge between transcription factors and RNA polymerase II. Genetic deletion of subunit 1 (Med1) results embryonic lethality, due large part to impaired cardiac development. We first established that Med1 is dynamically expressed development disease, with marked upregulation both human murine failing hearts. To determine if deficiency protects against stress, we generated two...
Aging and many illnesses injuries impair skeletal muscle mass function, but the molecular mechanisms are not well understood. To better understand mechanisms, we generated studied transgenic mice with muscle-specific expression of growth arrest DNA damage inducible α (GADD45A), a signaling protein whose in rises during aging wide range injuries. We found that GADD45A induced several cellular changes characteristic atrophy, including reduction mitochondria oxidative capacity, selective...
Widespread changes in cardiac gene expression occur during heart failure, yet the mechanisms responsible for coordinating these remain poorly understood. The Mediator complex represents a nodal point modulating transcription by bridging chromatin-bound factors with RNA polymerase II activity; it is reversibly regulated its cyclin-dependent kinase 8 (Cdk8) submodule. Here, we identified increased Cdk8 protein human failing explants and determined consequence of this increase cardiac-specific...
ABSTRACT L‐type Ca 2+ channels are macromolecular protein complexes in neurons and myocytes that open response to cell membrane depolarization supply for regulating gene transcription vesicle secretion triggering contraction. include a pore‐forming α an auxiliary β subunit, subunit openings regulated by cellular through mechanism involving the ‐sensing calmodulin (CaM) CaM binding motifs cytoplasmic C terminus. Here we show these “autoagonists” increase subunit. The domains necessary...