A5021097392- Hemoglobinopathies and Related Disorders
- Genetic and Kidney Cyst Diseases
- Renal and related cancers
- Erythrocyte Function and Pathophysiology
- Iron Metabolism and Disorders
- Genetic Syndromes and Imprinting
- Biomedical Research and Pathophysiology
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Hedgehog Signaling Pathway Studies
- Blood groups and transfusion
- Animal Genetics and Reproduction
- RNA and protein synthesis mechanisms
- Hemoglobin structure and function
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Kruppel-like factors research
- Heme Oxygenase-1 and Carbon Monoxide
- Microtubule and mitosis dynamics
- Biochemical and Molecular Research
- Neurogenetic and Muscular Disorders Research
- Bacterial Genetics and Biotechnology
- HIV/AIDS drug development and treatment
- Genomics and Phylogenetic Studies
- Pancreatic function and diabetes
Montreal Clinical Research Institute
2013-2023
Université de Montréal
2011-2021
Hôpital Jeanne de Flandre
2015
Centre Oscar Lambret
2015
McGill University
2014
Institute for Research in Immunology and Cancer
2009
Park University
2008
Columbia University
1987-1997
Boston Children's Hospital
1994
The Honourable Society of Lincoln's Inn
1985
Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for treatment ADPKD. We report that induced in cysts mouse and human Genetic deletion miR-17∼92 cluster inhibits cyst proliferation PKD progression four orthologous, including two long-lived, models Anti-miR-17 attenuates growth short-term long-term models. inhibition also suppresses primary ADPKD cultures derived from multiple donors....
The pathogenetic mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) remain to be elucidated. While there is evidence that Pkd1 gene haploinsufficiency and loss of heterozygosity can cause cyst formation in mice, paradoxically high levels expression have been detected the kidneys ADPKD patients. To determine whether gain function a process, bacterial artificial chromosome (Pkd1-BAC) was modified by homologous recombination solely target sustained preferentially adult...
Prevention of red cell K+ and water loss is a therapeutic strategy for sickle disease. We have investigated in vitro vivo the effects clotrimazole (CLT) miconazole (MIC) on transgenic mice cells expressing hemoglobin SAD. CLT blocked Gardos channel (ID50 75 +/- 22 nM; n = 3) A23187-induced dehydration Hbbs/Hbbthal SAD 1 mouse erythrocytes vitro. Oral treatment with (160 mg/kg per d) MIC (100 inhibited both control (Hbbs/Hbbthal) mice. In only, content increased, mean corpuscular...
We have recently reported the isolation of a class mutants (called thy-) that is both resistant to arabinosyl cytosine and auxotrophic for thymidine. thy- 5- 10-fold elevated pool dCTP are deficient in synthesis dTTP as an apparent consequence single mutation gene ribonucleoside-diphosphate reductase (2'-deoxyribonucleoside-diphosphate:oxidized-thioredoxin 2'-oxidoreductase, EC 1.17.4.1). Here we show three independent lines 50-fold higher frequency rate spontaneous two genetic markers,...
The human beta-globin and G gamma-globin genes are expressed at different stages of development also show distinct temporal patterns expression when transferred into the mouse germ line. In transgenic mice, gene is only in fetal adult erythroid cells, whereas active embryonic cells. Previous experiments suggested that 3' sequences were important for this paper we directly demonstrate presence an enhancer 3'-flanking region gene. First, deletion between 605 895 bp, to poly(A) site, results a...
K-Cl cotransport activity in rbc is a major determinant of volume and density. Pathologic activation erythroid sickle cell disease contributes to dehydration sickling. To address the roles individual cotransporter isoforms homeostasis, we disrupted Kcc1 Kcc3 genes mice. As was undiminished Kcc1(-/-) mice, decreased Kcc3(-/-) almost completely abolished mice lacking both isoforms, conclude that mouse mediated largely by KCC3. Whereas either or were normal density, Kcc1(-/-)Kcc3(-/-) exhibited...
While high levels of Pkd1 expression are detected in tissues patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from Pkd1-BAC modified by introducing silent tag via homologous recombination to target sustained wild-type genomic within the native tissue and temporal regulation. These mice specifically overexpressed transgene extrarenal renal...
Polycystin-1 (Pc1) cleavage at the G protein-coupled receptor (GPCR) proteolytic site (GPS) is required for normal kidney morphology in humans and mice. We found a complex pattern of endogenous Pc1 forms by GPS cleavage. generates not only heterodimeric cleaved full-length (Pc1(cFL)) which N-terminal fragment (NTF) remains noncovalently associated with C-terminal (CTF) but also novel form (Pc1(deN)) NTF becomes detached from CTF. Uncleaved (Pc1(U)) resides primarily endoplasmic reticulum...
In this study, we identified a BET bromodomain (BRD) protein, Brd4, not only as novel epigenetic regulator of autosomal dominant polycystic kidney disease (ADPKD) but also client protein Hsp90. We found that Brd4 was upregulated in Pkd1 mutant mouse renal epithelial cells and tissues. This upregulation appears to result from the chaperone activity Hsp90 escape proteasomal degradation. further identify is an upstream expression c-Myc which has been all rodent models PKD ADPKD patients with...
The SBM mouse is a unique transgenic model of polycystic kidney disease (PKD) induced by the dysregulated expression c-myc in renal tissue. In situ hybridization analysis demonstrated intense signal for transgene overlying tubular cystic epithelium mice. Renal proliferation index kidneys was 10-fold increased over nontransgenic controls correlating with presence epithelial hyperplasia. specificity proliferative potential cells substitution proto-oncogene c-fos or transforming growth factor...
The human G gamma-globin and beta-globin genes are expressed in erythroid cells at different stages of development, previous studies have shown that the two cloned also a differential stage-specific manner transgenic mice. gene is only murine embryonic cells, while active fetal adult stages. In this study, we analyzed mice carrying series hybrid which upstream, intragenic, or downstream sequences were contributed by gene. We found 5'G gamma/3'beta globin containing upstream from initiation...
During development and erythropoiesis, globin gene expression is finely modulated through an important network of transcription factors chromatin modifying activities. In this report we provide in vivo evidence that endogenous Ikaros recruited to the human beta-globin locus targets histone deacetylase HDAC1 remodeling protein Mi-2 gamma-gene promoters, thereby contributing gamma-globin silencing at time gamma- transcriptional switch. We show for first interacts with GATA-1 enhances binding...
Deoxygenation of sickle erythrocytes activates a cation permeability unknown molecular identity (Psickle), leading to elevated intracellular [Ca(2+)] ([Ca(2+)](i)) and subsequent activation K(Ca) 3.1. The resulting erythrocyte volume decrease elevates hemoglobin S (HbSS) concentration, accelerates deoxygenation-induced HbSS polymerization, increases the likelihood cell sickling. Deoxygenation-induced currents sharing some properties Psickle have been recorded from in whole configuration.We...
Growth factor independence 1b (GFI1B) is a DNA binding repressor of transcription with vital functions in hematopoiesis. Gfi1b-null embryos die at midgestation very likely due to defects erythro- and megakaryopoiesis. To analyze the full functionality Gfi1b, we used conditionally deficient mice that harbor floxed Gfi1b alleles inducible (Mx-Cre, Cre-ERT) or erythroid specific (EpoR-Cre) Cre expressing transgenes. In contrast germline knockout, EpoR-Cre mediated ablation allows gestation, but...
The thy-mutator phenotype of Chinese hamster ovary cells is distinguished by increased intracellular levels dCTP, auxotrophy for thymidine, and elevated spontaneous mutational rates.To determine the biochemical lesion responsible this complex phenotype, enzymes synthesis dCTP dTTP were investigated.Levels ribonucleotide reductase dCMP deaminase identical in mutant wild type strains.In contrast, CTP synthetase activity extracts from thy-strains was consistently altered that 50% enzyme...
Abstract The role of c ‐ myc has been well‐studied in gene regulation and oncogenesis but remains elusive murine development from midgestation. We determined function during kidney development, organogenesis, homeostasis by conditional loss induced at two distinct phases nephrogenesis, embryonic day (e) 11.5 e17.5. Deletion early metanephric mesenchyme (e11.5) led to renal hypoplasia e15.5 e17.5 that was sustained until adulthood (range, 20–25%) and, hence, reproduced the human pathologic...
The Krüppel-like factor 1 (KLF1) and KLF2 positively regulate embryonic β-globin expression have additional overlapping roles in (primitive) erythropoiesis. KLF1(-/-) KLF2(-/-) double knockout mice are anemic at day 10.5 (E10.5) die by E11.5, contrast to single knockouts. To investigate the combined of KLF1 primitive erythropoiesis, profiling E9.5 erythroid cells was performed. A limited number genes had a significantly decreasing trend wild-type, KLF1(-/-), mice. Among these, gene for Myc...