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是医师科学家，其职业专注于为患者开发改进的护理 镰状细胞疾病（SCD）。急性胸部综合征（ACS）代表严重的，潜在的致命 SCD患者发生的炎症性肺损伤综合征。 ACS分享了许多功能 与急性肺损伤有关的炎症性肺损伤是SCD的第二大最常见原因 住院是急性和慢性SCD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。越来越多的欣赏是ACS是急性缺氧诱导的 针对多种外源性侮辱或触发因素，靶向肺内皮的肺损伤综合征 导致肺红细胞螯合，夸张的炎症反应，表达增加 粘附分子和肺血管功能的损害。在这个高度翻译的建议中我们 将解决以下假设：ACS的血管靶向遗传和基因组策略将导致更好 了解ACS的病理生物学，在SCD患者中产生新型的ACS生物标志物并产生 用于改善这种毁灭性健康差异的血管特异性疗法。为了解决这一假设， 特定目的＃1我们将识别并验证潜在功能的新型单核苷酸多态性 （SNP）和表观遗传修饰符调节ACS敏感性。特定目标＃2将询问坏死作用 作为鼠AC中的分子和治疗靶标。在特定目标中＃3发现并验证生化和 SCD患者死亡率的ACS风险和基因组签名的遗传坏死生物标志物。 这些高度转化的方法共同识别出新的目标和生物标志物的承诺 可能会为ACS患者提供更好的治疗选择。