A5073205256- Genetic and Kidney Cyst Diseases
- Cellular transport and secretion
- Biomedical Research and Pathophysiology
- Diet and metabolism studies
- Renal Diseases and Glomerulopathies
- Lipid Membrane Structure and Behavior
- Renal and related cancers
- Genetic Syndromes and Imprinting
- Erythrocyte Function and Pathophysiology
- Pancreatic function and diabetes
- Hedgehog Signaling Pathway Studies
- Microtubule and mitosis dynamics
- Metabolism and Genetic Disorders
- Endoplasmic Reticulum Stress and Disease
- Glycosylation and Glycoproteins Research
- Renal cell carcinoma treatment
- Diet, Metabolism, and Disease
- RNA Research and Splicing
- Nuclear Structure and Function
- Botulinum Toxin and Related Neurological Disorders
- Ion channel regulation and function
- Tuberous Sclerosis Complex Research
- Ubiquitin and proteasome pathways
- Venomous Animal Envenomation and Studies
- Mitochondrial Function and Pathology
University of California, Santa Barbara
2015-2024
Institut thématique Génétique, génomique et bioinformatique
2005-2018
Neuroscience Institute
2013
Cleveland Clinic Lerner College of Medicine
2002-2005
Cleveland Clinic
2000-2004
University of California, San Francisco
1996-2000
University of Kentucky
1998
Memorial Sloan Kettering Cancer Center
1998
University of San Francisco
1995
University of Cologne
1990-1994
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...
Ketogenic diets have been widely used for weight loss and are increasingly in the management of type 2 diabetes. Despite evidence that ketones multiple positive effects on kidney function, common misconceptions about ketogenic diets, such as high protein content acid load, prevented their widespread use individuals with impaired function. Clinical trial focusing major adverse events is sparse. The aim this review to explore a diet, an emphasis pleiotropic actions ketones, health. Given...
We have analyzed conserved domains in t-SNAREs [soluble N -ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors the target membrane], proteins that are believed to be involved fusion of transport vesicles with their membrane. By using a sensitive computer method, generalized profile we were able identify new homology domain is common two families previously identified act as t-SNAREs, syntaxin and SNAP-25 (synaptosome-associated 25 kDa) families, which therefore...
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...
Syntaxins, integral membrane proteins that are part of the ubiquitous fusion machinery, thought to act as target receptors during process vesicle docking and fusion. Several isoforms syntaxin family have been previously identified in mammalian cells, some which localized plasma membrane. We investigated subcellular localization these putative syntaxins polarized epithelial characterized by presence distinct apical basolateral domains. Syntaxins 2, 3, 4 were found be endogenously present...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProteolipid protein (PLP) of CNS myelin: positions free, disulfide-bonded, and fatty acid thioester-linked cysteine residues implications for the membrane topology PLPThomas Weimbs Wilhelm StoffelCite this: Biochemistry 1992, 31, 49, 12289–12296Publication Date (Print):December 15, 1992Publication History Published online1 May 2002Published inissue 15 December...
Mutations in polycystin-1 (PC1) lead to autosomal-dominant polycystic kidney disease (ADPKD), a leading cause of renal failure for which no treatment is available. PC1 an integral membrane protein, has been implicated the regulation multiple signaling pathways including JAK/STAT pathway. Here we show that membrane-anchored activates STAT3 JAK2-dependent manner, tyrosine phosphorylation and transcriptional activity. The C-terminal cytoplasmic tail can undergo proteolytic cleavage nuclear...
Autosomal-dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease, and no approved treatment available in the United States to slow progression. The mammalian target rapamycin (mTOR) signaling pathway aberrantly activated cysts, while mTOR inhibitors are highly effective rodent models, clinical trials ADPKD have been disappointing due dose-limiting extrarenal side effects. Since known be regulated by nutrients cellular energy status, we hypothesized that...
Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation these findings (NCT04680780). Sixty-six patients were randomized a KDI arm (ketogenic diet [KD] or water fasting [WF]) the control group. Both induce significant ketogenesis on basis blood and breath acetone measurements. Ninety-five percent (KD) 85% (WF) report as...
We have investigated the controversial involvement of components SNARE (soluble N-ethyl maleimide–sensitive factor [NSF] attachment protein [SNAP] receptor) machinery in membrane traffic to apical plasma polarized epithelial (MDCK) cells. Overexpression syntaxin 3, but not syntaxins 2 or 4, caused an inhibition TGN transport and recycling, leads accumulation small vesicles underneath membrane. All other tested steps were unaffected by 3 overexpression. Botulinum neurotoxin E, which cleaves...
Activation of the mammalian target rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD rodent models, but clinical trials have not shown benefit, possibly a result low tissue concentrations at clinically tolerable doses. To overcome this limitation, we synthesized folate-conjugated form (FC-rapa) that taken up by folate receptor–mediated endocytosis and cleaved intracellularly to...
The rate of disease progression in autosomal-dominant (AD) polycystic kidney (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized prevalent form renal insult accelerate cystic and investigated tubular crystal deposition. report calcium oxalate (CaOx) deposition led to rapid tubule dilation, activation PKD-associated signaling pathways, hypertrophy segments along the affected nephrons. Blocking mTOR blunted this response...
In polarized epithelial cells, syntaxin 3 localizes to the apical plasma membrane and is involved in fusion of trafficking pathways. We show that contains a necessary sufficient targeting signal centered around conserved FMDE motif. Mutation any three critical residues within this motif leads loss specific targeting. Modeling based on known structure 1 revealed these are exposed surface three-helix bundle. Syntaxin does not require binding Munc18b. Instead, recruits Munc18b membrane....
Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow progression. Mutations gene coding for polycystin-1 (PC1) underlie majority cases but function PC1 has remained poorly understood. We have previously shown that regulates transcriptional activity signal transducer activator transcription-6 (STAT6). Here we show STAT6 aberrantly activated cyst-lining cells PKD mouse models....
Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to failure autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer activator of 3) was shown be activated cyst-lining cells ADPKD PKD mouse models may drive growth, but the mechanisms leading persistent activation are unknown. A proteolytic fragment PC1 corresponding cytoplasmic tail, PC1-p30, is overexpressed ADPKD. Here, we show that PC1-p30 interacts with...