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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：
10594936
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/10594936
关键词：
Address Animal Model Animals Apoptosis Apoptotic Blood Vessels Cell Proliferation Cell Separation 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 Lesion Link Lung Mediating Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Organ Pathogenesis Pathology Patients Phenotype Predisposition Progressive Disease Proliferating 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 improved 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.

项目摘要肺动脉高压（pulmonary hypertension，PH）是一种以肺血管阻力进行性增加为特征的疾病和闭塞性肺血管重塑，导致右心肥大、衰竭和过早死亡。死亡血管重塑和闭塞性血管病变形成的潜在机制仍然存在不清楚特发性肺动脉高压患者存在基因突变和变异 (PAH)和PAH伴先天性心脏病。然而，内皮SOX 17在调节细胞凋亡中的机制作用，肺血管重构在PH发病机制中的作用尚未见报道。我们假设内皮细胞 S0X17缺陷导致E2F1信号传导的激活，这有助于内皮细胞过度增殖和我们将1）确定内皮SOX 17在PH发病机制中的新作用，使用多种转基因小鼠和大鼠模型研究PH的发病机制。2)描述分子机制内皮SOX 17缺陷下游介导肺血管重塑和PH和3）探索靶向E2F1信号传导的翻译潜力。完成我们提出的研究将提供一个新的有效治疗PH患者的治疗策略。