A5050250465- Genetic and Kidney Cyst Diseases
- Renal and related cancers
- Biomedical Research and Pathophysiology
- Hedgehog Signaling Pathway Studies
- Renal Diseases and Glomerulopathies
- Pluripotent Stem Cells Research
- Urological Disorders and Treatments
- Genetic Syndromes and Imprinting
- Organ Donation and Transplantation
- Sphingolipid Metabolism and Signaling
- Renal cell carcinoma treatment
- Atherosclerosis and Cardiovascular Diseases
- Tissue Engineering and Regenerative Medicine
- Animal Genetics and Reproduction
- Microtubule and mitosis dynamics
- Developmental Biology and Gene Regulation
- Angiogenesis and VEGF in Cancer
- Prenatal Screening and Diagnostics
- Genomics and Chromatin Dynamics
- Adenosine and Purinergic Signaling
- Signaling Pathways in Disease
- Acute Lymphoblastic Leukemia research
- Reproductive Biology and Fertility
- Immune cells in cancer
- Lysosomal Storage Disorders Research
Johnson & Johnson (United States)
2024
Sanofi (United States)
2020-2024
Janssen (United States)
2021-2023
Framingham State University
2012
Sanofi (France)
2012
Harvard University
1999-2004
Boston Children's Hospital
1999-2004
Roswell Park Comprehensive Cancer Center
1992-2004
Whitehead Institute for Biomedical Research
2003
Massachusetts Institute of Technology
2003
The early development of the metanephric kidney is characterized by induced differentiation mesenchymal cells into a stem cell population that undergoes to epithelial transformation in response stimuli from ureteric bud. Wilms' tumor suppressor gene, Wt1, required for complete this developmental program. In absence WT1, prospective mesenchyme appears, but becomes apoptotic, and outgrowth bud Wolffian duct does not occur. Therefore, examination Wt1 −/− embryos allows determination those...
Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle proliferation. Although no effective therapy for the treatment is currently available, possible mechanism-based approaches beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell connection using CDK-inhibitor R-roscovitine showed arrest in jck cpk models that not orthologous human ADPKD. To evaluate whether CDK inhibition approach will translate into...
ABSTRACT. The Wilms’ tumor suppressor gene WT1 encodes a zinc finger protein that is required for urogenital development. In the kidney, most highly expressed in glomerular epithelial cells or podocytes, which are an essential component of filtering system. Human subjects heterozygous point mutations develop renal failure because formation scar tissue within glomeruli. relationship between expression podocytes during development and scarring not well understood. this study, transgenic mice...
The WT1 tumor suppressor gene is a zinc finger-containing transcription factor which required for development of the kidney and gonads. A mammal-specific alternative splicing event within this results in presence or absence 17-amino-acid sequence protein. To determine function vivo, targeting was utilized to specifically eliminate exon encoding mice. Mice lacking 5 develop normally. Adult mice are viable fertile, females capable lactation.
Development of novel therapies for polycystic kidney disease (PKD) requires assays that adequately reflect biology and are adaptable to high-throughput screening. Here we describe an embryonic cystic organ culture model demonstrate a new mutant allele the Pkd1 gene ( tm1Bdgz ) modulates cystogenesis in this model. Cyst formation induced by cAMP is influenced dosage allele: −/− cultures develop larger area compared with +/+ counterparts, while +/− show intermediate phenotype. A similar...
Genetic forms of polycystic kidney diseases (PKDs), including nephronophthisis, are characterized by formation fluid-filled cysts in the kidneys and progression to end-stage renal disease. No therapies currently available treat cystic diseases, making it imperative dissect molecular mechanisms search therapeutic targets. Accumulating evidence suggests a pathogenic role for glucosylceramide (GlcCer) multiple PKD. It is not known, however, whether other structural glycosphingolipids (GSLs) or...
Polycystic kidney diseases (PKDs) are genetic characterized by renal cyst formation with increased cell proliferation, apoptosis, and transition to a secretory phenotype at the expense of terminal differentiation. Despite recent progress in understanding PKD pathogenesis emergence potential therapies, key molecular mechanisms promoting cystogenesis not well understood. Here, we demonstrate that including endoplasmic reticulum stress, oxidative damage, compromised mitochondrial function all...
Development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (ADPKD) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes associated with disease. Using Pkd1 conditional knockout mouse, we demonstrate subtly altering timing extent deletion can have significant impact on origin severity cyst formation. postnatal day 1 or 2 results in cysts arising from both cortical medullary regions, whereas days 3–8...
ABSTRACT The transcription start site and DNA sequence elements required for the induction of Pax3 expression in differentiating P19 embryonal carcinoma cells have been localized. These consist a promoter additional located within 1.6 kbp 5′ to site. Sequence this region are also sufficient mediate dorsal restriction neural tube somites transgenic mice throughout hindbrain trunk. Additional anterior migrating myoblasts 14 This contains element(s) that repress ventral body wall mesoderm tail bud.
The Wt1 gene, originally identified as a tumor suppressor gene associated with Wilms' tumors, encodes zinc finger containing transcription factor expressed during gonadal and kidney development. Although appears to be required for development, no reproductive defects were observed in outbred females heterozygous targeted mutation Wt1. In contrast, litters obtained from +/− on strain 129/Sv inbred genetic background. Ovaries smaller mice produced fewer ova, but transplanted ovaries able...
Abstract Bardet–Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting multi-systemic manifestations. Here, we show the first time that monosialodihexosylganglioside accumulates in Bbs2−/− cilia, indicating impairment glycosphingolipid (GSL) metabolism BBS. Consequently, tested whether pathology mice can be reversed by underlying ciliary defect via...
While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism driving organ dysfunction. Here, we used a small molecule inhibitor glucosylceramide synthase to modulate GSL levels three mouse models distinct pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic (Nphs2 cKO). At tissue level, identified core immune-enriched transcriptional signature...
Abstract Diabetic kidney disease (DKD) is the leading cause of end‐stage disease. DKD a heterogeneous with complex pathophysiology where early endothelial dysfunction associated progression. The Tie2 receptor and Angiopoietin 1 2 ligands are critical for maintaining cell permeability integrity. signaling negatively regulated by specific transmembrane Vascular Endothelial Protein Tyrosine Phosphatase (VEPTP). Genetic deletion VEPTP protects from hypertension diabetes induced renal injury in...
The early development of the metanephric kidney is characterized by induced differentiation mesenchymal cells into a stem cell population that undergoes to epithelial transformation in response stimuli from ureteric bud. Wilms' tumor suppressor gene, Wt1, required for complete this developmental program. In absence WT1, prospective mesenchyme appears, but becomes apoptotic, and outgrowth bud Wolffian duct does not occur. Therefore, examination Wt1 −/− embryos allows determination those...
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end stage renal (ESRD). Studies in 1990s showed that levels two glycosphingolipids—glucosylceramide (GL-1) and lactosylceramide—were higher kidneys PKD patients mouse models than those healthy controls.