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

镰状细胞病急性肺损伤的细胞和分子机制

• 批准号: 9069964
• 负责人: Michael R. DeBaun
• 金额: $ 190.98万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069964
• 关键词: Acute Lung Injury; Biomedical Research; Cause of Death; Clinical Data; Clinical Research; Clinical Trials Design; Communities; Development; Doctor of Philosophy; Foundations; Genetic Markers; Genetic Polymorphism; Genomics; Health; Hematology; Heme; Hemoglobinopathies; Hemolysis; High School Student; Human; Human Resources Development; Incidence; Individual; Link; Lung; Mentors; Molecular; Morehouse School of Medicine; Mus; Phase I Clinical Trials; Physicians; Positioning Attribute; Research; Research Personnel; Research Project Grants; Research Training; Role; Scientist; Severities; Sickle Cell; Sickle Cell Anemia; Skills Development; Solid; TLR4 gene; Testing; Therapeutic; Tissues; Training; Training Programs; Translational Research; abstracting; acute chest syndrome; career awareness; career development; design; drug candidate; endothelial dysfunction; experience; heme a; improved; inhibitor/antagonist; lung injury; minority student; novel; novel marker; novel therapeutic intervention; novel therapeutics; phase I trial; pre-clinical; prevent; programs; research study; skill acquisition; summer research

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)

描述（由申请人提供）： 埃默里血红蛋白病研究卓越中心 (CEHR) 致力于通过发现影响 ACS 的关键分子和细胞机制以及人类多样性的遗传标记，针对 SCD 急性胸部综合征 (ACS) 的主要死因开发新的治疗方法和生物标志物，从而改善镰状细胞病 (SCD) 患者的健康，并培养我们社区在转化研究、意识和职业方面的能力 生物医学研究的管道。我们的首要科学假设是，血红素（组织损伤和溶血的产物）通过与 Toll 样受体 4 (TLR4) 的相互作用诱发 ACS。埃默里大学 CEHR 组建了一个由遗传学家、血液科医生和科学家以及肺生物学家组成的多学科团队，严格检验这一假设，并探索其在三个相互关联的具体目标中的治疗潜力：[1] 定义细胞和分子机制，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 ACS 发展中的作用，并为新疗法生成临床前数据。 [3] 识别与 ACS 发生率和严重程度相关的遗传多态性。转化研究技能发展核心旨在培训临床研究领域的医学博士和博士科学家，并为他们提供指导研究经验，使他们成为独立研究者。 MD学者的培训将强调I期临床试验的设计、执行和分析，学者将参与研究项目中出现的候选药物的I期试验的设计。这位正在接受临床研究和基因组学培训的博士学者也将参与 CEHR 的研究工作。针对高中生的镰状细胞夏季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结合。总之，埃默里大学 CEHR 拟议的项目将严格测试一种新的肺损伤机制，确定干扰该机制的候选药物，并在科学和人力资源方面为开发预防或治疗镰状细胞病 ACS 的全新治疗方法奠定坚实的基础。 （摘要完）