The proposed research is designed to determine the prevalence and risk factors of pulmonary hypertension (PHTN) in children and adolescents with sickle cell disease (SCD), and to determine the role of the hypoxic response in its pathogenesis. The present proposal is based on 3 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 vaso-occlusive episodes. PHTN is a complication of conditions marked by chronic hypoxia, and also 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 mediated 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.
Aim 1. Determine the prevalence, risk factors and clinical consequences of pulmonary hypertension (PHTN) in children and adolescents with sickle cell disease (SCD).
Aim 2. Elucidate the pathophysiology of PHTN in SCD by comparing proliferative vascular responses mediated by i) HIF-regulated pathways and ii) nitric oxide-scavenging from the clinical to cellular level in patients with SCD and patients with Chuvash polycythemia (CP).
Aim 3. Using micro array analysis and high throughput genotyping, examine patterns of gene expression and candidate gene polymorphisms of the HIF-mediated hypoxic response in SCD and CP patients with and without PHTN.
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