PUSH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项研究旨在确定镰状细胞病SCD儿童和青少年肺动脉高压 PHTN的患病率和危险因素，并确定缺氧反应在其发病机制中的作用。本提案基于三个假设。首先，SCD相关PHTN的问题可能开始于儿童和青春期。其次，SCD相关PHTN的发病机制可能不仅包括慢性溶血性疾病中一氧化氮清除的作用，还包括与严重贫血和反复血管闭塞发作相关的慢性缺氧的后果。PHTN是以慢性缺氧为标志的病症的并发症，也是Chuvash红细胞增多症CP的并发症，Chuvash红细胞增多症CP是一种先天性氧感受障碍，其中缺氧反应在缺氧不存在的情况下组成性上调。第三，我们假设，SCD相关的PHTN的病理生理学可能是阐明通过比较增殖血管反应介导的缺氧诱导因子和一氧化氮清除SCD和CP患者根据肺动脉高压的存在或不存在。根据SCD和CP的临床和病理生理特征的比较，我们假设，除了增加一氧化氮清除，改变表达的基因或基因缺氧诱导因子HIF调节的PHTN在SCD和CP的病理生理学是中央。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research is designed to determine the prevalenc and risk factors of pulmonry hypertension (PHTN) in children and adolescents with sickle cell disease (SCD), and to determine the role of the hypoxic response in it s pathogenesis. The present proposal is based on three postulates. First, the problem of SCD-associated PHTN may begin during childhood and adolescence. Second, the pathogenesis of SCD-associated PHTN may include not only the effects of nitric oxide scavenging in a chronic hemolytic disorder, but also the consequences of chronic hypoxia related to severe anemia and to repeated vasoocclusive episodes. PHTN is a complication of conditions marked by chronic hypoxia, and aslo a complication of Chuvash polycythemia (CP), a congenital disorder of oxygen sensing in which the hypoxic response is constitutively up regulated in the absence of hypoxia. Third, we postulate that the pathophysiology of SCD-associated PHTN may be elucidated by comparing proliferative vascular responses medicated by HIF and by nitric oxide scavenging in patients with SCD and CP according to the presence or absence of pulmonary hypertension. Based on a comparison of the clinical and pathophysiologic features of SCD and CP, we hypothesize that, in addition to increased nitric oxide-scavenging, altered expression of a gene or genes regulated by hypoxia inducible factor (HIF) is central to the pathophysiology of PHTN in both SCD and CP.