Asthma and Nocturnal Hypoxemia in Sickle Cell Anemia

我们的总体目标是阐明两种常见合并症的生理、遗传和分子方面，哮喘和夜间氧饱和度降低，增加镰状细胞性贫血（SCA）的疼痛发生率。在单独的研究中，我们已经表明，与没有这种情况的儿童相比，患有SCA和哮喘或夜间去饱和的儿童的疼痛率增加。此外，我们的研究小组证明，与没有SCA的小鼠相比，SCA小鼠模型对缺氧诱导的肺血管充血有明显的易感性。不幸的是，我们不知道哮喘、夜间去饱和血和SCA患者肺部疾病之间的相互关系。我们提出三个相互关联的项目。第一个和第二个临床项目将描述哮喘和夜间去饱和与SCA相关发病率之间关系的生理基础。第一个项目还将获得1800名参加无症状性脑梗死（SIT）试验的SCA儿童的DMA和临床信息。我们将进行一项病例对照研究，评估与哮喘相关的基因是否会增加疼痛和ACS发作的风险。基础科学项目将进行实验，旨在确定哮喘和夜间低氧血症分别或共同增加转基因SCA小鼠模型肺损伤的分子机制。我们将检验三个总体假设：1)哮喘的表型和基因型特征是SCA患儿疼痛和ACS发作的危险因素；2) SCA患儿夜间血饱和度降低可改变哮喘对SCA发病率的影响；3)慢性气道炎症和夜间缺氧分别或共同增加hbss诱导的SCA模型小鼠肺损伤。总之，临床和基础科学家高度互动合作的结果将使人们对肺部疾病的机制有新的认识，从而为针对这一弱势群体的靶向治疗提供坚实的基础。

Our overall goal is to elucidate the physiologic, genetic, and molecular aspects of two common co-morbid conditions, asthma and nocturnal oxygen desaturation, that increase the incidence rate of pain in sickle cell anemia (SCA). In separate studies, we have shown children with SCA and either asthma or nocturnal desaturation have an increased pajn rate when compared to children without the condition. Also, our group demonstrated that in a murine model of SCA there was significant susceptibility to hypoxia-induced pulmonary vasocongestion when compared to mice without SCA. Unfortunately, we do not know the interrelationship if any, between asthma, nocturnal desaturation and lung disease in SCA. We propose three interrelated projects. The first and second clinical projects will delineate the physiological basis for the association of asthma and nocturnal desaturation with SCA related morbidity. The first project will also obtain DMA and clinical information from 1800 children with SCA participating in the Silent Cerebral Infarct (SIT) Trial. We will perform a case-control study evaluating whether genes associated with asthma increase the risk of pain and ACS episodes. The basic science project will have experiments aimed at defining the molecular mechanisms by which asthma and nocturnal hypoxemia, separately and together, increase lung injury in a transgenic SCA murine model. We will test three global hypotheses: 1) phenotypic and genotypic features of asthma are risk factors for pain and ACS episodes in children with SCA; 2) nocturnal desaturation in children with SCA modifies the effect of asthma on morbidity in SCA; and 3) chronic airway inflammation and nocturnal hypoxia, separately and together, increase HbSS-induced lung injury in a murine SCA model. Taken together, the results of this highly interactive collaboration of clinical and basic scientists will permit new insights into the mechanisms of lung disease, thus providing a strong foundation for targeted therapy for this vulnerable group.