A5018238937- Receptor Mechanisms and Signaling
- Hemoglobinopathies and Related Disorders
- Renal and related cancers
- FOXO transcription factor regulation
- RNA and protein synthesis mechanisms
- Mast cells and histamine
- Folate and B Vitamins Research
- Glycosylation and Glycoproteins Research
- RNA modifications and cancer
- Biotin and Related Studies
- Microbial Metabolites in Food Biotechnology
- Biofuel production and bioconversion
- Protein Structure and Dynamics
- Zebrafish Biomedical Research Applications
- Vitamin C and Antioxidants Research
- Ubiquitin and proteasome pathways
- Cellular transport and secretion
- Enzyme Production and Characterization
- CRISPR and Genetic Engineering
- Coenzyme Q10 studies and effects
- Genetic and Kidney Cyst Diseases
- Cellular Mechanics and Interactions
- Cancer, Hypoxia, and Metabolism
- Biomarkers in Disease Mechanisms
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
University of Pittsburgh
2012-2022
University of Pittsburgh Medical Center
2021
Discovery Institute
2017
Georgetown University Medical Center
2006
Georgetown University
2006
University of Illinois Chicago
2006
University of Michigan
1997-2003
Cleveland Clinic
1996-1997
University of Mumbai
1988-1990
The current model of serine protease diversity theorizes that the earliest molecules were simple digestive enzymes gained complex regulatory functions and restricted substrate specificities through evolution. Among chymase group proteases are convert angiotensin I to II, as well others simply degrade angiotensins. An ancestral reconstructed with use phylogenetic inference, total gene synthesis, protein expression had efficient specific II-forming activity (turnover number, about 700 per...
Planar cell polarity (PCP) regulates alignment required for collective movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question role cilium PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and movement, but underlying mechanism is unknown. Here we show Wdpcp can by direct modulation actin cytoskeleton. These studies were made possible recovery...
Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for treatment of various central nervous system disorders including drug abuse. In particular, considerable attention mGluR5 field has been devoted to ligands bind allosteric modulatory site, distinct from site primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) its analogue...
Human chymase and rat chymase-1 are mast cell serine proteases involved in angiotensin II (Ang II) formation degradation, respectively. Previous studies indicate that both these enzymes have similar P1 P2 preferences, which the major determinants of specificity. Surprisingly, despite occurrence optimal residues at Phe8 downward arrow Tyr4 bonds (where arrow, indicates scissile bond peptide substrates) Ang I (DRVYIHPFHL), human cleaves with an approximately 750-fold higher catalytic...
The CTP:glycerol-3-phosphate cytidylyltransferase (GCT) of <i>Bacillus subtilis</i> has been shown to be similar in primary structure the CTP:phosphocholine cytidylyltransferases several organisms. To identify residues this family that function catalysis, conserved hydrophilic amino acid plus a tryptophan GCT were mutated alanine. most dramatic losses activity occurred with H14A and H17A; these histidine are part an H<i>X</i>GH sequence found class I aminoacyl-tRNA synthetases. <i>k</i>...
NADPH oxidase 4 (NOX4) regulates endothelial inflammation by producing hydrogen peroxide (H2O2) and to a lesser extent O2•-. The ratio of NOX4-derived H2O2 O2•- can be altered coenzyme Q (CoQ) mimics. Therefore, we hypothesize that cytochrome b5 reductase 3 (CYB5R3), CoQ abundant in vascular cells, inflammatory activation. To examine CYB5R3 vivo, created tamoxifen-inducible endothelium-specific Cyb5r3 knockout mice (R3 KO). Radiotelemetry measurements systolic blood pressure showed systemic...
PACSIN/Syndapin proteins are membrane-active scaffolds that participate in endocytosis. The structure of the Drosophila Syndapin N-terminal EFC domain reveals a crescent shaped antiparallel dimer with high affinity for phosphoinositides and unique membrane-inserting prong upon concave surface. Combined structural, biochemical reverse genetic approaches zebrafish define an important role orthologue, Pacsin3, early formation notochord during embryonic development. In pacsin3-morphant embryos,...
No therapies have been shown to accelerate recovery or prevent fibrosis after acute kidney injury (AKI). In part, this is because most therapeutic candidates be given at the time of and diagnosis AKI usually made too late for drugs efficacious. Strategies enhance post-AKI repair represent an attractive approach address this. Using a phenotypic screen in zebrafish, we identified 4-(phenylthio)butanoic acid (PTBA), which promotes proliferation embryonic progenitor cells (EKPCs), PTBA methyl...
Background & AimsThere is a pressing need to develop effective preventative therapies for post–endoscopic retrograde cholangiopancreatography pancreatitis (PEP). We showed that early PEP events are induced through the calcium-activated phosphatase calcineurin and global deletion abolishes in mice. A crucial question whether acinar cell controls initiation of vivo.MethodsWe used mouse model examined effects vivo cell-specific by either generating conditional knockout line or infusing novel...
Reactivation of genes normally expressed during organogenesis is a characteristic kidney regeneration. Enhancing this reactivation could potentially be therapeutic target to augment The inductive events that drive in zebrafish are similar the initial steps mammalian organogenesis. Therefore, quantifying embryonic signals development an attractive strategy for discovery potential novel modalities accelerate Lim1 homeobox protein, Lhx1, marker also regenerating kidneys after injury. Using...
The bacterial enzyme, glycerol-3-phosphate cytidylyltransferase (GCT), is a model for mammalian cytidylyltransferases and member of large superfamily nucleotidyltransferases. Dimeric GCT from Bacillus subtilis displays unusual negative cooperativity in substrate binding appears to form products only when both active sites are occupied by substrates. Here we describe complex with the product, CDP-glycerol, crystal structure which bound sulfate serves as partial mimic second pyrophosphate....
Uroplakin (UP)3a is critical for urinary tract development and function; however, its role in these processes unknown. We examined the function of UP3a-like protein Upk3l, which was expressed at apical surfaces epithelial cells that line pronephric tubules (PTs) zebrafish pronephros. Embryos treated with upk3l-targeted morpholinos showed decreased pronephros function, attributed to defects PT cell morphogenesis polarization including: loss an brush border associated phospho-ERM proteins,...
CTPglycerol-3-phosphate cytidylyltransferase (GCT) catalyzes the synthesis of CDP-glycerol for teichoic acid biosynthesis in certain Gram-positive bacteria. This enzyme is a model family that includes enzymes synthesize CDP-choline and CDP-ethanolamine phosphatidylcholine phosphatidylethanolamine biosynthesis. We have used quenching intrinsic tryptophan fluorescence to measure binding affinities substrates GCT from Bacillus subtilis. Binding either CTP or glycerol-3-phosphate was biphasic,...
Zebrafish embryos are a near-ideal animal model for drug discovery because of their high genetic and physiological similarity to mammals, small size, fecundity, optical transparency. The latter properties make zebrafish at larval stages especially suited high-content analysis throughput screening (HTS). However, inherent biological complexity the inability screen multiple specimens in single well present challenge HTS limiting replicates variability often prevent assays from reaching...
One of the key mechanisms vascular smooth muscle cell (SMC) dilation occurs through nitric oxide (NO)-dependent induction soluble guanylyl cyclase (sGC) by means its β-subunit. Herein, we are first to identify Forkhead box subclass O protein 4 (FoxO4) as a transcriptional regulator GUCY1B3 expression, which codes for sGCβ in human and animal SMCs. This discovery will likely have important implications future usage antihypertensive vasodilatory therapies target NO production, sGC, or FoxO...
Pathogens enhance their survival during infections by manipulating host defenses. Francisella tularensis evades innate immune responses, which we have found to be dependent on an understudied gene ybeX (FTL_0883/FTT_0615c). To understand the function of YbeX, sought protein interactors in F. subsp. holarctica live vaccine strain (LVS). An unstudied co-immunoprecipitated with recombinant is a predicted glycosyltransferase DXD-motif. There are up four genomic copies this identical sequence...