Vascular-targeting genomic and genetic strategies for acute chest syndrome

急性胸部综合征的血管靶向基因组和遗传策略

• 批准号: 10213108
• 负责人: Roberto F. Machado
• 金额: $ 58.84万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-05 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213108
• 关键词: Acute; Acute Lung Injury; Address; Admission activity; Biochemical Genetics; Biological Markers; Blood Vessels; Cause of Death; Cell Adhesion Molecules; Cessation of life; Chronic; DNA methylation profiling; Development; Endothelium; Epigenetic Process; Erythrocytes; Functional disorder; Funding; Genetic; Genetic Markers; Genomic approach; Genomics; Hemin; Hospitalization; Hypoxia; Impairment; Individual; Inflammatory; Inflammatory Response; Lead; Lung; Mediator of activation protein; Modeling; Molecular Target; Morbidity - disease rate; Mus; Pathway interactions; Patient Care; Patients; Physicians; Predisposition; Regulation; Risk; Risk Factors; Role; Scientist; Severities; Sickle Cell Anemia; Single Nucleotide Polymorphism; Syndrome; Systems Biology; Therapeutic; Vascular Diseases; Vascular Permeabilities; acute chest syndrome; career; clinical care; exome sequencing; genetic approach; genomic signature; health disparity; improved; insight; lung injury; mortality; next generation sequencing; novel; novel strategies; pre-clinical; premature; response; targeted biomarker; therapeutic target; tool; translational approach; translational study

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 identify and validate potentially functional novel single nucleotide polymorphisms (SNPs) and epigenetic modifiers that modulate ACS susceptibility. Specific Aim #2 will interrogate necroptosis as a molecular and therapeutic target in murine ACS. In Specific Aim #3 discover and validate biochemical and genetic necroptosis-centric biomarkers of ACS risk and a genomic signature for mortality in SCD patients. 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.

抽象的 该应用程序的 PI 是一位医师科学家，其职业重点是改善患者护理 患有镰状细胞病（SCD）。急性胸部综合症 (ACS) 是一种严重的、可能致命的疾病 SCD 患者发生炎症性肺损伤综合征。 ACS 具有许多相同的功能 与急性肺损伤相关的炎性肺损伤，是 SCD 的第二常见原因 住院治疗是急性和慢性 SCD 发病和死亡的主要原因，是 SCD 的主要原因 入住 ICU 并过早死亡。人们越来越认识到 ACS 是一种急性缺氧引起的疾病 针对多种外源性损伤或触发因素而针对肺内皮的肺损伤综合征 导致肺红细胞隔离、炎症反应过度、表达增加 粘附分子和肺血管功能受损。在这个高度转化的提案中，我们 将解决以下假设：针对 ACS 的血管靶向遗传和基因组策略将带来更好的结果 了解 ACS 的病理学，在 SCD 患者中生成新的 ACS 生物标志物并产生 血管特异性疗法可改善这种破坏性的健康差距。为了解决这个假设，在 具体目标#1 我们将鉴定并验证具有潜在功能的新型单核苷酸多态性 （SNP）和调节 ACS 易感性的表观遗传修饰因子。具体目标#2将询问坏死性凋亡 作为小鼠 ACS 的分子和治疗靶点。在具体目标#3 中发现并验证生化和 以遗传坏死性凋亡为中心的 ACS 风险生物标志物和 SCD 患者死亡率的基因组特征。 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， 可能会为 ACS 患者带来更好的治疗选择。