Effect of XCT790 on Aortic Valves (AV) in NOTCH1 (N1)-Haploinsufficient Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE152061 | GEO | 2021/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:Effect of XCT790 on Aortic Valves (AV) in NOTCH1 (N1)-Haploinsufficient Mice
| PRJNA638168 | ENA
Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells; In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Experiment Overall Design: In the study, we hybridized RNA from E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells to Affymetrix MOE430 2 GeneChip® arrays.
2008-10-21 | E-GEOD-11040 | biostudies-arrayexpress
Project description:Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice heterozygous for the orthologous factor, although the source of this discrepancy is unknown. The inability to accurately model human disease in mice impedes the study of complex phenotypes and critically limits the discovery and testing of potential therapeutics. Laboratory mice have longer telomeres (>40 kilobases (kb)) compared to humans (~5-15 kb), potentially protecting them from age-related disease caused by haploinsufficiency. In humans, heterozygous non-sense mutations in the transcription factor, NOTCH1 (N1), lead to severe age-dependent aortic valve (AV) calcification. However, mice heterozygous for N1 do not develop calcific AV disease (CAVD)5. Here, we show that telomere shortening is sufficient to elicit age-dependent cardiac valve disease in N1+/- mice that closely mimics the human disease and that progressive shortening correlates with severity of disease, extending to AV thickening in the neonate. N1 haploinsufficiency led to increased proliferation in valves that further reduced telomere length. Calcified AVs exhibited downregulation of osteoclast factors and upregulation of pro-calcific regulatory nodes concordant with gene network alterations in human N1 heterozygous endothelial cells. Dysregulated genes in valves were enriched for those that have promoters normally contacted by telomere looping. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease that may have broader implications and provides an in vivo model in which to test therapeutic candidates to prevent or delay the progression of CAVD.
2017-08-22 | GSE83963 | GEO
Project description:We explored gene expression profile of human aortic valves in patients with or without aortic stenosis. The dataset that we generated constitutes a large-scale quantitative measurements of gene expression in normal and stenotic human valves. The goal was to compare gene expression levels between the two groups and identified a list of genes that are up- or down-regulated in aortic stenosis. Keywords: disease state analysis Gene expression was performed on ten normal and ten aortic stenosis valves
2009-07-09 | E-GEOD-12644 | biostudies-arrayexpress
Project description:RNA-seq on human primary AV ECs from patients with healthy tricuspid, calcified tricuspid, or calcified bicuspid AVs
2021-01-01 | GSE151312 | GEO
Project description:Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in formation of portions of the atrial and ventricular septae, and generation of thin, pliable valves. The transcription factor Gata4 is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling. Keywords: genetic modification
2006-07-14 | GSE5298 | GEO
Project description:We explored gene expression profile of human aortic valves in patients with or without aortic stenosis. The dataset that we generated constitutes a large-scale quantitative measurements of gene expression in normal and stenotic human valves. The goal was to compare gene expression levels between the two groups and identified a list of genes that are up- or down-regulated in aortic stenosis. Keywords: disease state analysis
2009-07-09 | GSE12644 | GEO
Project description:Discovery of small molecules that correct gene networks dysregulated in human disease may allow identification of therapies that treat disease at its fundamental basis by leveraging mechanism-based data. Here, we report the first broad gene network-based drug screen, which led to discovery of a drug candidate that effectively treats aortic valve disease in an animal model. We previously reported haploinsufficiency of NOTCH1 (N1) as a genetic cause of human aortic valve thickening and calcification, the third most common form of heart disease, and described the resulting gene network dysregulation in human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs). We exposed isogenic N1+/+ or N1+/– iPSC-derived ECs to each of 1595 small molecules or control and developed a machine learning approach that accurately distinguished WT or N1-haploinsufficient cells based on expression of 119 genes assayed by targeted RNA-sequencing. 9 small molecules corrected the gene network of N1+/– ECs sufficiently to be classified as WT. Among hits tested in vivo, the estrogen receptor-related alpha inverse agonist XCT790 significantly reduced aortic valve thickening, calcification, and stenosis in N1-haploinsufficient mice with shortened telomeres, which model the range of age-dependent cardiac disease observed in humans. This strategy, made feasible by human iPSC technology, next generation sequencing approaches, and machine learning, may represent a more effective path for drug discovery compared to conventional screening approaches.
2021-01-01 | GSE125299 | GEO
Project description:Aortic valves are collected from patients with severe aortic valve stenosis undergoing aortic valve replacement at the Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Quebec City, Canada. From this biobank collection, transcriptomic analyses from 240 aortic valves were performed. All valves were tricuspid and had a fibro-calcific remodeling score of 3 or 4. RNA was extracted from valve leaflets and gene expression evaluated using the Illumina HumanHT-12 v4 Expression BeadChip. The main objective of this study was to perform a large-scale expression quantitative trait loci (eQTL) mapping study on human aortic valves.
2018-03-14 | GSE102249 | GEO
Project description:Calcified aortic valve leaflets (CAVs) were explanted from patients with severe aortic valve stenosis undergoing aortic valve replacement at the Department of Cardiovascular Surgery, Union Hospital, affiliated to Tongji Medical College. Control non-calcified aortic valves with normal echocardiographic analyses were obtained during heart transplant procedures. RNA was extracted from valve leaflets and gene expression evaluated using the Arraystar Human mRNA Array. This study aimed to perform the expression analysis of mRNA on human aortic valves.
2020-07-26 | GSE155119 | GEO