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: 9925265
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925265
• 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; 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.

摘要 该应用程序的PI是一名医生-科学家，其职业重点是为患者开发更好的护理 镰状细胞病（SCD）急性胸部综合征（ACS）是一种严重的，可能致命的疾病。 SCD患者发生炎性肺损伤综合征。ACS与 炎性肺损伤与急性肺损伤相关，是SCD的第二大常见原因 住院治疗是导致急性和慢性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。越来越多的人认识到ACS是一种急性缺氧诱导的 靶向肺内皮细胞的肺损伤综合征对多种外源性损伤或触发物的反应 导致肺部红细胞隔离，过度的炎症反应， 粘附分子和肺血管功能受损。在这个高度翻译的建议中，我们 将解决这一假设，即针对ACS的血管靶向遗传和基因组策略将导致更好的 了解ACS的病理生物学，在SCD患者中产生新的ACS生物标志物， 血管特异性疗法来改善这种毁灭性的健康差异。为了解决这个问题，在 具体目标#1我们将鉴定和验证潜在的功能性新的单核苷酸多态性 （SNPs）和调节ACS易感性的表观遗传修饰剂。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，发现并验证生物化学和 ACS风险的以坏死性凋亡为中心的遗传生物标志物和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鉴定新的靶标和生物标志物， 可能为ACS患者提供更好的治疗选择。