A5087257594- Renal Diseases and Glomerulopathies
- Chronic Kidney Disease and Diabetes
- Genetic and Kidney Cyst Diseases
- Renal and related cancers
- Pancreatic function and diabetes
- Liver physiology and pathology
- Cellular transport and secretion
- Cell Adhesion Molecules Research
- Acute Kidney Injury Research
- Lymphatic System and Diseases
- Histone Deacetylase Inhibitors Research
- Chronic Lymphocytic Leukemia Research
- Renal Transplantation Outcomes and Treatments
- Dialysis and Renal Disease Management
- Biomedical Research and Pathophysiology
- Organ Transplantation Techniques and Outcomes
- Autoimmune Bullous Skin Diseases
- SARS-CoV-2 and COVID-19 Research
- Wnt/β-catenin signaling in development and cancer
- Long-Term Effects of COVID-19
- Nuclear Structure and Function
- Lymphatic Disorders and Treatments
- Phagocytosis and Immune Regulation
- Genetics and Neurodevelopmental Disorders
- Receptor Mechanisms and Signaling
Yale University
2015-2025
Akron General Medical Center
2024
Cleveland Clinic
2024
National Institutes of Health
2020
Harvard University
2020
Rockefeller University
2020
Brigham and Women's Hospital
2020
Cornell University
2020
Princeton University
2020
Federation of American Societies for Experimental Biology
2020
Polycystic kidney disease (ADPKD) results from failure of the to properly maintain three-dimensional structure after loss either polycystin-1 or -2. Mice with selective inactivation Pkd1 during embryogenesis develop profound renal cystic and die within 3 weeks birth. In this model, cysts form exclusively cells in which Cre recombinase is active, but apparent pace cyst expansion varies by segment cell type. Intercalated do not participate despite presence cilia up at least postnatal day 21....
Podocytes are specialized cells that play an integral role in the renal glomerular filtration barrier via their foot processes. The processes form a highly organized structure, disruption of which causes nephrotic syndrome. Interestingly, several similarities have been observed between mechanisms govern podocyte organization and mediate neuronal synapse development. Dynamin, synaptojanin, endophilin functional partners synaptic vesicle recycling interconnected actions clathrin-mediated...
Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between podocyte and basement membrane requires integrins, defects in either α3 or β1 integrin, α3β1 ligand laminin result nephrotic syndrome murine models. large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to actin cytoskeleton. Here, we found mice lacking specifically podocytes display severe proteinuria, foot...
Growth factors such as hepatocyte growth factor (HGF) are highly up-regulated during development and following renal injury known to induce marked morphogenic actions in cultured tubular epithelial cells, including scattering, migration, single cell branching morphogenesis, multicellular tubulogenesis. In the present study, we demonstrate that HGF stimulates cells express neutrophil gelatinase-associated lipocalin (Ngal), a member of family secreted proteins has recently been shown...
Focal adhesion kinase (FAK) is a nonreceptor tyrosine that plays critical role in cell motility. Movement and retraction of podocyte foot processes, which accompany injury, suggest focal disassembly. To understand better the mechanisms by process effacement leads to proteinuria kidney failure, we studied function FAK podocytes. In murine models, glomerular injury led activation FAK, followed effacement. Both podocyte-specific deletion pharmacologic inactivation abrogated induced injury....
Ureteric bud (UB) branching during kidney development determines the final number of nephrons. Although hepatocyte growth factor and its receptor Met have been shown to stimulate morphogenesis in explanted embryonic kidneys, loss expression is lethal early embryogenesis without obvious abnormalities. Met(fl/fl);HoxB7-Cre mice, which lack selectively UB, were generated found a reduction nephron number. These mice increased Egf both adult kidney, exogenous can partially rescue defect seen...
We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, leading cause end-stage disease. mRNA expression profiling from mouse glomeruli was linked Connectivity Map databases, identifying HDAC1 HDAC2 with differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment valproic acid (a class I inhibitor) or SAHA pan-HDAC mitigated degree proteinuria...
The progression of proteinuric kidney diseases is associated with podocyte loss but the mechanisms underlying this process remain unclear. Podocytes re-enter cell cycle to repair double-stranded DNA (dsDNA) breaks. However, unsuccessful can result in podocytes crossing G1/S checkpoint and undergoing abortive cytokinesis. In study, we identified Pfn1 as indispensable maintaining glomerular integrity - its tissue-specific mouse results severe proteinuria failure. Our suggest that phenotype due...
Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by variety of injurious stimuli that lead to dysfunction/loss glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein crumbs homolog-2, have been shown cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified 2-generation Indian kindred (DUK40595) with biopsy-proven SRNS/FSGS compound heterozygous mutation CRB2...
Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests after podocyte injury, endoplasmic reticulum stress response is activated, but molecular mechanisms involved incompletely defined. In a mouse model, we confirmed injury induces and upregulated unfolded protein pathways, which have been shown to mitigate damage by preventing accumulation of misfolded proteins in reticulum. Furthermore, simultaneous podocyte-specific...
Cell-matrix interactions and podocyte intercellular junctions are key for maintaining the glomerular filtration barrier. Vinculin, a cytoplasmic protein, couples actin filaments to integrin-mediated cell-matrix adhesions cadherin-based junctions. Here, we examined role of vinculin in podocytes by generation podocyte-specific knockout mouse. Mice lacking had increased albuminuria foot process effacement following injury vivo. Analysis primary isolated from mutant mice revealed defects cell...
Background Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because its role in modulating DNA damage and preventing premature senescence. Methods Germline podocyte-specific Hdac1 2 ( / ) double-knockout mice were generated to examine the importance these enzymes development. Results Podocyte-specific loss resulted severe proteinuria, kidney failure, collapsing glomerulopathy. -deprived podocytes...
Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient allele expression affects transplant outcomes is unclear. To test APOL1 independently correlate outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney cohorts: Genomics of Chronic Allograft Rejection (GOCAR) Clinical Trials Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion African ancestry, or pAFR)...
Polycystin 1, the product of PKD1 gene, is mutated in autosomal dominant polycystic kidney disease, a disease characterized by renal cyst formation and progressive failure. We show that expression C-terminal domain human polycystin-1 (PKD1-CT) triggers spreading isolated inner medullary collecting duct cells, process mediated Erk. As cells spread, PKD1-CT localizes to cell-extracellular matrix contacts, interacts with focal adhesion proteins Fak paxillin, stimulates phosphorylation, paxillin...
Following organ injury, morphogenic epithelial responses can vary depending on local cell density.In the present study, role of confluence in determining responsiveness renal cells to dedifferentiating signals hepatocyte growth factor (HGF) was examined.Increasing resulted a greater tendency organize into tubes and significant decrease migratory HGF.Analysis downstream signaling revealed that HGF receptor c-Met equally activated confluent nonconfluent following stimulation but...