Vascular-targeted genomic and genetic strategies for acute chest syndrome

描述（由申请人提供）：本申请的PI是一名医师兼科学家，其职业重点是为镰状细胞病（SCD）患者开发改进的护理。急性胸综合征（ACS）是SCD患者发生的一种严重的、可能致命的炎症性肺损伤综合征。ACS具有与急性肺损伤相关的炎性肺损伤的许多特征，是SCD住院的第二大常见原因；是急性和慢性SCD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，ACS是一种急性缺氧诱导的肺损伤综合征，在多种外源性损伤或触发下，以肺内皮为靶点，导致肺红细胞隔离、炎症反应夸大、粘附分子表达增加和肺血管功能受损。在这个高度转化的建议中，我们将解决ACS的血管靶向遗传和基因组策略将导致更好地理解ACS的病理生物学，在SCD患者中产生新的ACS生物标志物，并产生血管特异性治疗来改善这种破坏性的健康差异的假设。为了解决这一假设，在Specific Aim #1中，我们将确定调节ACS易感性的新型单核苷酸多态性，并产生具有ACS风险的SNP面板。特异性目标2将完善和验证SCD患者ACS风险的全基因组、以血管为中心的基因组。在Specific Aim #3中，我们将探讨血管通透性调控通路基因和蛋白在小鼠ACS和ALI中的作用。总之，这些高度转化的方法有望确定新的靶点和生物标志物，从而为ACS患者提供更好的治疗选择。

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.