A5021707377- Renal Diseases and Glomerulopathies
- Endoplasmic Reticulum Stress and Disease
- Renal and related cancers
- Phagocytosis and Immune Regulation
- Cancer Cells and Metastasis
- Autophagy in Disease and Therapy
- Connective Tissue Growth Factor Research
- Biomarkers in Disease Mechanisms
- Pancreatic function and diabetes
- Chronic Kidney Disease and Diabetes
- Gut microbiota and health
- Metabolism, Diabetes, and Cancer
- 3D Printing in Biomedical Research
- Dialysis and Renal Disease Management
- Renin-Angiotensin System Studies
- TGF-β signaling in diseases
- Tissue Engineering and Regenerative Medicine
- Digestive system and related health
- MicroRNA in disease regulation
- Genetics, Aging, and Longevity in Model Organisms
- Atherosclerosis and Cardiovascular Diseases
- Cell Adhesion Molecules Research
- Wnt/β-catenin signaling in development and cancer
- Coenzyme Q10 studies and effects
- Diabetes Treatment and Management
Pfizer (United States)
2017-2023
Biogen (United States)
2016-2018
University of Washington
2016-2017
California Institute for Regenerative Medicine
2017
Biogen (Switzerland)
2014
MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides distribute kidney inhibit miR-21 function when administered subcutaneously evaluated therapeutic potential these anti-miR-21 chronic disease. In a murine model Alport nephropathy, did not...
Background Kidney injury is characterized by persisting inflammation and fibrosis, yet mechanisms which inflammatory signals drive fibrogenesis remain poorly defined. Methods RNA sequencing of fibrotic kidneys from patients with CKD identified a metabolic gene signature comprising loss mitochondrial oxidative phosphorylation expression concomitant increase in regulators enzymes glycolysis under the control PGC1 α MYC transcription factors, respectively. We modeled this switch vivo ,...
Fibrosis of vital organs is a major public health problem with limited therapeutic options. Mesenchymal cells including microvascular mural (pericytes) are progenitors scar-forming myofibroblasts in kidney and other organs. Here we show pericytes healthy kidneys have active WNT/β-catenin signaling responses that markedly up-regulated following injury. Dickkopf-related protein 1 (DKK-1), ligand for the WNT coreceptors low-density lipoprotein receptor-related proteins 5 6 (LRP-5 LRP-6) an...
Fibrotic disease is associated with matrix deposition that results in the loss of organ function. Pericytes, precursors myofibroblasts, are a source pathological collagens and may be promising targets for treating fibrogenesis. Here, we have shown pericytes activate TLR2/4- MyD88-dependent proinflammatory program response to tissue injury. Similarly classic immune cells, NLRP3 inflammasome, leading IL-1β IL-18 secretion. Released signals through pericyte MyD88 amplify this response....
Patient-derived organoid (PDO) models offer potential to transform drug discovery for inflammatory bowel disease (IBD) but are limited by inconsistencies with differentiation and functional characterization. We profiled molecular cellular features across a range of intestinal examined establishment epithelial barrier.Patient-derived organoids or monolayers were generated from control IBD patient-derived colon ileum molecularly functionally profiled. Biological technical replicates...
Abstract Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD- UMOD ), a leading hereditary disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD- carrying mutation, we show that autophagy/mitophagy and mitochondrial biogenesis impaired, cGAS-STING activation tubular injury. Moreover, demonstrate inducible overexpression of mesencephalic...
Pentraxin-2 (PTX-2), also known as serum amyloid P component (SAP/APCS), is a constitutive, antiinflammatory, innate immune plasma protein whose circulating level decreased in chronic human fibrotic diseases. Here we show that recombinant PTX-2 (rhPTX-2) retards progression of kidney disease Col4a3 mutant mice with Alport syndrome, reducing blood markers failure, enhancing lifespan by 20%, and improving histological signs disease. Exogenously delivered rhPTX-2 was detected macrophages but...
Uromodulin-associated kidney disease (UAKD) is caused by mutations in the uromodulin (UMOD) gene that result a misfolded form of UMOD protein, which normally secreted nephrons. In UAKD patients, mutant poorly and accumulates ER distal epithelium, but its role progression largely unknown. Here, we modeled accumulation mice expressing murine equivalent human p.Cys148Trp point mutation (UmodC147W/+ mice). Like affected humans, these UmodC147W/+ developed spontaneous progressive with organ...
The identification of the cellular origins myofibroblasts has led to discovery novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated role innate immune signaling this process. In mice, renal injury-induced activation pericytes, which are precursors attached endothelial cells, upregulated expression TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. live rat kidney slices,...
Connective tissue growth factor (CTGF), a matrix-associated protein with four distinct cytokine binding domains, has roles in vasculogenesis, wound healing responses, and fibrogenesis is upregulated fibroblasts myofibroblasts disease. Here, we investigated the role of CTGF fibrogenic cells. In mice, tissue-specific inducible overexpression by kidney pericytes had no bearing on nephrogenesis or homeostasis but exacerbated inflammation fibrosis after ureteral obstruction. These effects...
The intestinal epithelium comprises diverse cell types and executes many specialized functions as the primary interface between luminal contents internal organs. A key function provided by is maintenance of a barrier that protects individual from pathogens, irritating contents, microbiota. Disruption this can lead to inflammatory disease within mucosa, and, in more severe cases, sepsis. Animal models study permeability are costly not entirely predictive human biology. Here we present model...
Loss of the microvascular (MV) network results in tissue ischemia, loss function, and is a hallmark chronic diseases. The incorporation functional vascular with that host remains challenge to utilizing engineered tissues clinically relevant therapies. We showed vascular-bed-specific endothelial cells (ECs) exhibit differing angiogenic capacities, kidney (MVECs) being most deficient, sought explore underlying mechanism. Constitutive activation phosphatase PTEN MVECs resulted impaired PI3K/AKT...
ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, have gained interest as a model system with potentially high translational value progressive human disease. To thoroughly characterize this model, better understand how closely it recapitulates disease, we performed resolution longitudinal analysis of renal disease progression in spanning from early end stage Analyses included metabolic endpoints, histology ultrastructure, evaluation urinary biomarker...
Autosomal dominant tubulointerstitial kidney disease (ADTKD)-uromodulin (
Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD- UMOD ), one of the leading hereditary diseases, and Alzheimer’s etc. There are no targeted therapies. ADTKD is also a genetic form renal fibrosis chronic disease, which affects 500 million people worldwide. For first time, in our newly generated mouse model recapitulating human ADTKD- carrying deletion mutation, we show that...
Abstract The intestinal epithelium comprises diverse cell types and executes many specialized functions as the primary interface between luminal contents internal organs. A key function provided by is maintenance of a barrier that protects individual from pathogens, irritating contents, microbiota. Disruption this can lead to inflammatory disease within mucosa, and, in more severe cases, sepsis. Animal models study permeability are costly not entirely predictive human biology. Here we...
Abstract Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects T2D, for many patients these approaches do not sufficiently control disease. As a result, an emerging therapeutic strategy is to target pathobiological mechanisms downstream T2D derangement result in organ damage, morbidity, mortality afflicted individuals. One such proposed mechanism involves Protein Kinase C (PKC) family...