Pulmonary Hypertension in SCD

描述（由申请人提供）： 肺部并发症如肺动脉高压（pHTN）已成为发病率和死亡率的主要来源。杜克大学综合镰状细胞中心提供了一个大型的和良好的特征化的患者群体，研究SCD中pHTN的许多方面。我们提出的工作的长期目标是（1）增加我们对SCD中pHTN的自然史以及导致其发展的病理生理机制的理解;（2）确定可以改善这种破坏性并发症的过程的特定治疗干预措施。为此，我们将实现以下三个具体目标。目标1：我们将研究疾病进展的自然史和过程，以及确定SCD的疾病标志物和与pHTN相关的疾病修饰基因。我们将对另外200名患有SCD的患者进行pHTN筛查，并将在不少于2年至4年的随访期间研究>100名患有轻度重度pHTN和SCD的患者。研究将侧重于临床特征（项目1），以及疾病标志物和遗传多态性（项目2）。目标2：我们将确定两种治疗药物波生坦和输血对pHTN和其他肺和心血管功能参数以及SCD活动生物标志物的影响。我们将在60例轻度pHTN患者中进行一项波生坦（项目3）与安慰剂的随机试验。此外，我们将研究输血对中重度pHTN的影响（项目4）。目标3：我们将研究涉及NO，超氧化物和红细胞生物学（项目5）的基本病理生理机制，因为它们影响人类和动物的肺循环。这些目标的实现将提供一个更深入的了解SCD的发展和自然史的pHTN，帮助确定那些患者的pHTN的最大风险，阐明pHTN的发病机制，并提供指导有效治疗这种危及生命的综合征。 (End说明）

DESCRIPTION (provided by applicant): Pulmonary complications such as pulmonary hypertension (pHTN) have become a major source of both morbidity and mortality. The Duke-UNC Comprehensive Sickle Cell Center offers a large and well characterized patient population with which to study many aspects of pHTN in SCD. The long-term goals of our proposed work are (1) to increase our understanding of both the natural history of pHTN in SCD, as well as the pathophysiologic mechanisms leading to its development; and (2) to identify specific therapeutic interventions that can ameliorate the course of this devastating complication. To these ends, we will accomplish the following three Specific Aims. AIM 1: We will study the natural history and course of disease progression, as well as identify disease markers of SCD and disease-modifying genes associated with pHTN. We will screen 200 additional patients with SCD for pHTN and we will study >100 patients with mild severe pHTN and SCD during follow up periods of no less than two years and up to 4 years. Studies will focus on clinical characteristics (Project 1), as well as disease markers and genetic polymorphisms (Project 2). AIM 2: We will determine the effects of two therapeutic maneuvers-bosentan and transfusion-on pHTN and other parameters of pulmonary and cardiovascular function, as well as biomarkers of SCD activity. We will conduct a randomized trial of bosentan (Project 3) vs. placebo in 60 patients with mild pHTN. In addition, we will study the effects of transfusion on moderate-severe pHTN (Project 4). AIM 3: We will investigate basic pathophysiologic mechanisms involving NO, superoxide and red cell biology (Project 5), as they affect the pulmonary circulation in humans and animals. Achievement of these aims will provide a more in-depth understanding of the development and natural history of pHTN in SCD, help identify those patients at greatest risk for pHTN, elucidate pathogenetic mechanisms in pHTN, and provide guidance toward effective treatment of this life-threatening syndrome. (End of Description)