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Role of Endothelial SOX17 Deficiency in the Pathogenesis of Pulmonary Hypertension

内皮 SOX17 缺陷在肺动脉高压发病机制中的作用

基本信息

批准号：
10442975
负责人：
Zhiyu Dai
金额：
$ 47.98万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-20 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442975
关键词：
Address Animal Model Animals Apoptosis Apoptotic Blood Vessels Cell Proliferation Cell model Cessation of life DNA Sequence Alteration Data Development Disease Down-Regulation E2F transcription factors Endothelium Enhancers Failure Functional disorder Gene Mutation Genes Genetic Transcription Heart Heart Hypertrophy Hypertension Lead Lesion Link Lung Mediating Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Organ Pathogenesis Pathology Patients Phenotype Predisposition Progressive Disease Pulmonary Hypertension Pulmonary Vascular Resistance Rattus Reporting Repression Research Resistance Role SOX17 gene Signal Transduction Stress Structure Survival Rate Transgenic Mice Up-Regulation Vascular remodeling Western Blotting bone morphogenetic protein receptors cdc Genes congenital heart disorder effective therapy genetic variant in vivo innovation knock-down loss of function loss of function mutation mortality novel novel therapeutic intervention premature primary pulmonary hypertension promoter pulmonary arterial hypertension pulmonary artery endothelial cell pulmonary vascular remodeling right ventricular failure therapeutically effective transcription factor transcriptome sequencing translational potential treatment strategy

项目摘要

PROJECT SUMMARY Pulmonary hypertension (PH) is characterized by progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of vascular remodeling and obliterative vascular lesion formation remain unclear. Genetic mutations and variants were found in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the mechanistic role of endothelial SOX17 in regulating pulmonary vascular remodeling in the pathogenesis of PH has not been reported. We hypothesis that endothelial SOX17 deficiency leading to activation of E2F1 signaling which contributes to endothelial hyperproliferation and anti-apoptosis in the pathogenesis of PH. We will 1) define the novel role of endothelial SOX17 in the pathogenesis of PH using multiple transgenic mouse and rat models. 2) delineate the molecular mechanisms downstream of endothelial SOX17 deficiency in mediating pulmonary vascular remodeling and PH and 3) explore the translational potential of targeting E2F1 signaling. Completing our proposed study will provide a novel therapeutic strategy for the effective treatment of PH in patients.

项目总结