A5035200915- Enzyme-mediated dye degradation
- Genetic and Kidney Cyst Diseases
- Renal and related cancers
- Metal-Catalyzed Oxygenation Mechanisms
- Microbial Metabolism and Applications
- Genetic Syndromes and Imprinting
- Biochemical and biochemical processes
- MicroRNA in disease regulation
- Enzyme Structure and Function
- Animal Genetics and Reproduction
- CRISPR and Genetic Engineering
- melanin and skin pigmentation
- Circular RNAs in diseases
- Protein Structure and Dynamics
- Biomedical Research and Pathophysiology
- Urological Disorders and Treatments
- Cell Adhesion Molecules Research
- Chromosomal and Genetic Variations
- Dye analysis and toxicity
- Extracellular vesicles in disease
- Hedgehog Signaling Pathway Studies
- Enzyme Production and Characterization
- Metal complexes synthesis and properties
- Analytical chemistry methods development
- Cancer Mechanisms and Therapy
Johns Hopkins University
2008-2018
University of Freiburg
1982-2018
University of Waterloo
2018
Western Michigan University
2018
University of Kansas
2018
Shell (Japan)
2018
UL Solutions (United States)
2018
Geosyntec Consultants (United States)
2018
University of Houston
2018
Johns Hopkins Medicine
2004-2017
Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function PC1 has remained poorly understood. No preventive treatment for this available. Here, we show cytoplasmic tail interacts with tuberin, and mTOR pathway inappropriately activated cyst-lining epithelial cells human ADPKD patients mouse models. Rapamycin, an inhibitor mTOR, highly effective...
Hepatocellular carcinoma (HCC) is a common and deadly cancer. Most cases of HCC arise in cirrhotic/fibrotic liver, indicating that environment may play paramount role cancer genesis. Previous studies from our group others have shown that, desmoplastic cancers, there rich intercellular communication between activated, cancer‐associated fibroblasts cells. Moreover, extracellular vesicles (EVs), or exosomes, been identified as an important arm this platform. Finally, these EVs can carry...
Aberrant activation of the mammalian target rapamycin (mTOR) pathway occurs in polycystic kidney disease (PKD). mTOR inhibitors, such as rapamycin, are highly effective several rodent models PKD, but these result from mutations genes other than Pkd1 and Pkd2, which primary responsible for human autosomal dominant PKD. To address this limitation, we tested efficacy a mouse model that results conditional inactivation Pkd1. Mosaic deletion resulted PKD replicated characteristic features...
It has been shown recently that Trp171 of lignin peroxidase (LiP) is hydroxylated at the Cβ position [Blodig, W., Doyle, W. A., Smith, A. T., Winterhalter, K., Choinowski, and Piontek, K. (1998) Biochemistry 37, 8832−8838]. Comparative experiments, carried out on both wild-type fungal recombinant LiP isoenzyme H8 (LiPH8*), indicate process hydroxylation autocatalytic may be implicated in catalysis. The role this residue therefore examined using site-directed mutagenesis to obtain enzymes...
The primary structure of polycystin predicts a large integral membrane protein with multiple cell recognition motifs, but its function remains unknown. Insight into polycystin’s normal and role in the development autosomal dominant polycystic kidney disease (PKD1) requires assembly an extensive collection molecular reagents to examine expression create model systems for functional studies. Development these crucial has been complicated due presence transcriptionally active homologous loci....
Polycystin-1 (PC1) has an essential function in renal tubular morphogenesis and disruption of its causes cystogenesis human autosomal dominant polycystic kidney disease. We have previously shown that recombinant PC1 is cis-autoproteolytically cleaved at the G protein-coupled receptor proteolytic site domain. To investigate role cleavage vivo, we generated by gene targeting a Pkd1 knockin mouse (Pkd1(V/V)) expresses noncleavable PC1. The Pkd1(V/V) mice show hypomorphic phenotype,...
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic characterized by bilateral renal cyst formation. Both hyperproliferation and hypertrophy have been previously observed in ADPKD kidneys. Polycystin-1 (PC-1), large orphan receptor encoded the PKD1 gene mutated 85% of all cases, able to inhibit proliferation apoptosis. Here we show that overexpression PC-1 epithelial cells inhibits cell growth (size) cycle-independent manner due downregulation mTOR, S6K1, 4EBP1....
The heme‐containing glycoprotein lignin peroxidase (pI 4.15) has been crystallized at pH 4.0. structure of the from orthorhombic crystals determined by multiple isomorphous replacement. model comprises all 343 amino acids, one heme molecule, and three sugar residues. It refined to an R ‐factor 20.3%. chain fold residues 15 275 is in general similar those cytochrome c peroxidase. Despite binding same region a arrangement proximal distal histidine as significantly larger distance iron ion...
Aromatic peroxygenases (APOs) represent a unique oxidoreductase sub-subclass of heme proteins with peroxygenase and peroxidase activity were thus recently assigned distinct EC classification (EC 1.11.2.1). They catalyze, inter alia, oxyfunctionalization reactions aromatic aliphatic hydrocarbons remarkable regio- stereoselectivities. When compared cytochrome P450, APOs appear to be the choice enzymes for oxyfunctionalizations in organic synthesis due their independence from cellular...
The cancer microenvironment plays a central role in development, growth, and homeostasis. This paradigm suggests that fibroblasts support cancers, probably response to stimuli received from the cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated (CAFs) To this end, we extracted EVs according published protocols. were studied for their miR content by quantitative reverse-transcription polymerase chain reaction....
Abstract Primary cilia contain specific receptors and channel proteins that sense the extracellular milieu. Defective ciliary function causes ciliopathies such as autosomal dominant polycystic kidney disease (ADPKD). However, little is known about how large transmembrane traffic to cilia. Polycystin-1 (PC1) -2 (PC2), two ADPKD gene products, are co-localize where they act control proper tubular diameter. Here we describe PC1 PC2 must interact form a complex reach trans -Golgi network (TGN)...
Gene targeting has been used to create a variety of lines mice with <i>Pkd1</i> mutations that share many common features. Homozygous mutants invariably develop pancreatic and renal cysts if they survive day 15.5 post coitum die in either the fetal or perinatal period. In contrast, heterozygous are generally normal have few any cysts. These features limited utility these models as tools study pathogenesis cyst formation effect various therapeutic interventions on disease progression. This...
Polycystic kidney disease (PKD) describes a heterogeneous collection of disorders that differ significantly with respect to their etiology and clinical presentation. They share, however, abnormal tubular morphology as common feature, leading the hypothesis respective gene products may function cooperatively in pathway maintain integrity. To study pathobiology one major form human PKD, we generated mouse line floxed allele Pkhd1 , orthologue mutated autosomal recessive PKD. Cre-mediated...
Mutations in PKD1 cause the majority of cases autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, differentiation, and apoptosis, its lower biologic activity observed ADPKD might influence degree injury after renal ischemia/reperfusion. We induced ischemia/reperfusion 10- to 12-wk-old male noncystic Pkd1(+/-) wild-type mice. Compared with mice, heterozygous mice had higher fractional excretions sodium potassium serum creatinine 48 h. In...
Background Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of inherited renal failure that results from mutations in PKD1 and PKD2. The disorder characterized by focal cyst formation involves somatic mutation the wild type allele large fraction cysts. Consistent with two-hit mechanism, mice are homozygous for inactivating either Pkd1 or Pkd2 develop cystic kidneys, edema hemorrhage typically die midgestation. Cystic unlikely to be fetal loss since function not required...
Dye-decolorizing peroxidases (DyPs) belong to the large group of heme peroxidases. They utilize hydrogen peroxide catalyze oxidations various organic compounds. AauDyPI from Auricularia auricula-judae (fungi) was crystallized, and its crystal structure determined at 2.1 Å resolution. The mostly helical also shows a β-sheet motif typical for DyPs Cld (chlorite dismutase)-related structures includes complete polypeptide chain. At distal side molecule, flexible aspartate residue (Asp-168) plays...
Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095) leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before after P13 mice results distinct early- late-onset disease. Using a mouse model ADPKD carrying floxed alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation cyst formation applying transcriptomics metabolomics follow disease progression large number animals...