Effect of XCT790 on Aortic Valves (AV) in NOTCH1 (N1)-Haploinsufficient Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA638168 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11959729_1.fastq.gz | Fastqsanger.gz | |||
| SRR11959729_2.fastq.gz | Fastqsanger.gz | |||
| SRR11959730_1.fastq.gz | Fastqsanger.gz | |||
| SRR11959730_2.fastq.gz | Fastqsanger.gz | |||
| SRR11959731_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA-seq on aortic valves from WT vs N1-haploinsufficient telomere-shortened (generation 2 Terc-/-) mice with either healthy AVs or AV stenosis treated with control solvent or XCT790
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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.
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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.
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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. Experiment Overall Design: To further investigate the role of Gata4 in EC development, we specifically inactivated Gata4 in endothelium and endothelium-derived cushion mesenchyme. All mice were maintained in a mixed C57BL6/129 genetic background. Gata4wt/flox; T2Cre+ mice were crossed with Gata4flox/flox mice to yield Gata4flox/flox (CONTROL); T2Cre+ (Gata4T2del) (MUTANT) mice.
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