Vascular-targeted genomic and genetic strategies for acute chest syndrome

描述(由申请人提供)：此申请的PI是一名内科科学家，其职业重点是为镰状细胞病(SCD)患者开发更好的护理。急性胸部综合征(ACS)是一种严重的、可能致命的炎症性肺损伤综合征，发生于SCD患者。急性冠脉综合征具有与急性肺损伤相关的炎症性肺损伤的许多特征，是SCD住院的第二大常见原因；是SCD急慢性发病率和死亡率的主要原因，是SCD ICU入院和过早死亡的主要原因。越来越多的人认识到，急性冠脉综合征是一种以肺内皮细胞为靶点的急性缺氧性肺损伤综合征，对多种外源性损伤或触发做出反应，导致肺红细胞隔离、过度炎症反应、黏附分子表达增加和肺血管功能损害。在这项高度翻译的提案中，我们将解决这样的假设，即针对ACS的血管靶向遗传和基因组策略将导致更好地了解ACS的病理生物学，在SCD患者中产生新的ACS生物标记物，并产生针对血管的治疗方法来改善这种毁灭性的健康差距。为了解决这一假设，在特定的目标#1中，我们将识别调节急性冠脉综合征易感性的新的单核苷酸多态，并产生一个与急性冠脉综合征风险相关的SNP小组。具体目标2将提炼和验证全基因组范围的、以血管为中心的基因组对SCD患者急性冠脉综合征风险的影响。在特定的目标#3中，我们将询问血管通透性调节通路基因和蛋白在小鼠急性冠脉综合征和急性肺损伤中的作用。总之，这些高度翻译的方法有望识别新的靶点和生物标记物，可能为急性冠脉综合征患者带来更好的治疗选择。

DESCRIPTION (provided by applicant): The PI of this application is a physician-scientist 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 identify novel single nucleotide polymorphisms that modulate ACS susceptibility and generate an ACS risk- conferring SNP panel. Specific Aim #2 will refine and validate genome-wide, vascular-centric genomic of ACS risk in SCD patients. In Specific Aim #3 we will interrogate the involvement of vascular permeability-regulatory pathway genes and proteins in murine ACS and ALI. 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.