Cellular and Molecular Mechanisms of Acute Lung Injury in Sickle Cell Disease

描述(由申请人提供)： 埃默里血红蛋白病卓越研究中心(CEHR)致力于改善镰状细胞病(SCD)患者的健康，为SCD急性胸腔综合征(ACS)的主要死因开发新的治疗方法和生物标记物，通过发现影响SCD的关键分子和细胞机制以及人类多样性的遗传标记，并在我们的社区建立生物医学研究中的转化研究、意识和职业管道的能力。我们最重要的科学假设是，组织损伤和溶血的产物--血红素通过与Toll样受体4(TLR4)相互作用而诱导急性冠脉综合征。Emory CEHR汇集了一个由遗传学家、血液学医生和科学家以及肺生物学家组成的多学科团队，以严格测试这一假说，并从三个相互关联的具体目标探索其治疗潜力：[1]确定细胞和分子机制，以及血红素诱导的内皮功能障碍和肺损伤的抑制剂。[2]确定TLR4在SCD小鼠急性冠脉综合征发展中的作用，并为新的治疗方法产生临床前数据。[3]确定与急性冠脉综合征的发生率和严重程度相关的基因多态。翻译研究技能发展核心旨在培养临床研究方面的医学博士和博士科学家，并为他们提供指导研究经验，使他们成为独立的研究人员。对医学博士的培训将强调一期临床试验的设计、执行和分析，该学者将参与研究项目产生的候选药物(S)的一期试验的设计。这位博士生正在接受临床研究和基因组学方面的培训，也将参与CEHR的研究工作。针对高中生的镰刀细胞暑期研究培训计划与莫尔豪斯医学院针对少数族裔学生的强有力的职业发展计划相联系。总之，Emory CEHR的拟议项目将严格测试一种新的肺损伤机制，确定干扰它的候选药物，并在科学和人力资源方面为开发一种全新的治疗方法来预防或治疗镰状细胞疾病中的急性冠脉综合征奠定坚实的基础。(摘要结束)

DESCRIPTION (provided by applicant): The Emory Center of Excellence in Hemoglobinopathy Research (CEHR) aspires to improve the health of individuals with sickle cell disease (SCD) by developing novel therapeutics and biomarkers for the major cause of death in SCD acute chest syndrome (ACS), through the discovery of critical molecular and cellular mechanisms, and genetic markers of human diversity that influence ACS, and to build capacity in our community in translational research, awareness and career pipelines in biomedical research. Our overarching scientific hypothesis is that heme, a product of tissue damage and hemolysis induces ACS via interaction with toll-like receptor 4 (TLR4). The Emory CEHR assembles a multi-disciplinary team of geneticists, hematology physicians and scientists, and lung biologists to rigorously test this hypothesis and explore its therapeutic potential in three inter-related Specific Aims: [1] Define cellular and molecular mechanisms, and inhibitors of heme-induced endothelial dysfunction and lung injury. [2] Determine the role of TLR4 in the development of ACS in SCD mice and generate pre-clinical data for novel therapeutics. [3] Identify genetic polymorphisms associated with the incidence and severity of ACS. A Translational Research Skills Development Core aims to train an MD and a PhD scientist in clinical research and provide mentored research experience for them to become independent investigators. Training for the MD scholar will emphasize phase I clinical trial design, execution and analysis, and the scholar will participate in the design of a Phase I trial of candidate drug(s) emerging from the research project. The PhD scholar, pursuing training in clinical research and genomics, will also be positioned to participate in the research studies of the CEHR. The Sickle Cell Summer Research Training Program for high school students links with a robust program of career development for minority students at Morehouse School of Medicine. In summary, the proposed project of the Emory CEHR will rigorously test a novel mechanism of lung injury, identify candidate drugs that interfere with it, and lay a solid foundation - in both scientific and human resources - for the development of an entirely new therapeutic approach to preventing or treating ACS in sickle cell disease. (End of Abstract)