Asthma and Nocturnal Hypoxemia in Sickle Cell Anemia

我们的总体目标是阐明两种常见的共病条件-哮喘和夜间氧减饱和-增加镰状细胞性贫血(SCA)疼痛发生率的生理、遗传和分子方面。在单独的研究中，我们发现患有SCA和哮喘或夜间减饱和的儿童与没有这种情况的儿童相比有更高的PAJN发生率。此外，我们的小组还证明，与没有SCA的小鼠相比，在SCA的小鼠模型中，低氧诱导的肺血管充血具有显著的易感性。不幸的是，我们不知道哮喘、夜间减饱和和肺部疾病之间的相互关系。我们提出了三个相互关联的项目。第一个和第二个临床项目将描绘哮喘和夜间减饱和与SCA相关发病率之间联系的生理学基础。第一个项目还将获得参加无症状脑梗塞(SIT)试验的1800名患有SCA的儿童的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急性冠脉综合征发作的风险。基础科学项目将进行实验，旨在确定哮喘和夜间低氧血症在转基因SCA小鼠模型中单独和共同增加肺损伤的分子机制。我们将检验三个全球假说：1)哮喘的表型和基因特征是SCA儿童疼痛和ACS发作的危险因素；2)SCA儿童的夜间减饱和度改变了哮喘对SCA发病率的影响；3)慢性呼吸道炎症和夜间低氧单独和共同增加了HbSS诱导的小鼠SCA模型中的肺损伤。综上所述，临床和基础科学家高度互动的合作结果将使人们能够对肺部疾病的机制有新的见解，从而为这一脆弱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.