Vascular Targeting Genomic & Genetic Strategies for Acute Chest Syndrome

摘要 这个应用程序的PI是一名医生-科学家，职业生涯专注于开发更好的患者护理 患有镰状细胞病(SCD)。急性胸部综合征(ACS)代表着一种严重的、可能致命的 SCD患者发生炎性肺损伤综合征。ACS具有许多功能， 炎症性肺损伤与急性肺损伤相关，是SCD的第二大常见原因 住院，是SCD急慢性发病率和死亡率的主要原因，是SCD的主要原因 ICU入院和过早死亡。越来越多的人认识到，急性冠脉综合征是由急性缺氧引起的 以肺内皮细胞为靶点的肺损伤综合征对多种外源性损伤或触发的反应 导致肺红细胞隔离，一种夸大的炎症反应，表达增加 黏附分子和肺血管功能受损。在这份高度翻译的提案中，我们 将解决这样一种假设，即针对血管的遗传和基因组策略将导致更好的 了解急性冠脉综合征的病理生物学，在SCD患者中产生新的急性冠脉综合征生物标志物 血管特效疗法，以改善这一毁灭性的健康差距。为了解决这一假设，在 具体目标#1我们将测试和验证T细胞受体谱系作为修饰物和 急性冠脉综合征易感性的生物标志物。特定目标#2将询问RASA3作为分子靶标在 小鼠急性冠脉综合征。在具体目标#3中，我们将询问内皮细胞脂滴作为一种分子和 小鼠急性冠脉综合征的治疗靶点。总而言之，这些高度翻译的方法有望识别 可能为急性冠脉综合征患者提供更好治疗选择的新靶点和生物标志物。

ABSTRACT The PI of this application is a physician-scientists with a career focus on developing improved care for patients with sickle cell disease (SCD). The acute chest syndrome (ACS) represents a serious, potentially fatal inflammatory lung injury syndrome occurring in patients with SCD. ACS shares many features of the inflammatory lung injury associated with acute lung injury and is the second most common cause of SCD hospitalization, is a major cause of acute and chronic SCD morbidity and mortality, is the leading cause of SCD ICU admission and premature death. There is increasing appreciation that ACS is an acute hypoxia-induced lung injury syndrome targeting the lung endothelium in response to multiple exogenous insults or triggers leading to pulmonary erythrocyte sequestration, an exaggerated inflammatory response, increased expression of adhesion molecules and impairment of pulmonary vascular function. In this highly translational proposal we will address the hypothesis that vascular-targeted genetic and genomic strategies for ACS will lead to better understanding of the pathobiology of ACS, generate novel ACS biomarkers in SCD patients and produce vascular-specific therapies for ameliorating this devastating health disparity. To address this hypothesis, in Specific Aim #1 we will test and validate the potential of T-cell receptor repertoire profiling as modifiers and biomarkers of ACS susceptibility. Specific Aim #2 will interrogate the role of RASA3 as a molecular target in murine ACS. In Specific Aim #3 we will interrogate the role of endothelial cell lipid droplets as a molecular and therapeutic target in murine ACS. Together, these highly translational approaches hold the promise to identify novel targets and biomarkers that may lead to better treatment options for patients with ACS.