TRANSGENIC MODEL FOR SICKLE ACUTE CHEST SYNDROME

描述 (摘自申请者摘要)总体目标：培育一只动物 威胁生命的镰刀状急性胸部综合征(ACS)的模型 人类镰状细胞病的并发症，以研究病理生理学 和测试疗法。受过儿科训练的申请人 血液学-肿瘤学，建议学习肺部研究和 肺科医生指导下的内皮细胞黏附研究 还有一位血液学家。研究假设是急性冠脉综合征的病理生理学 包括红细胞(RBC)镰状和黏附、中性粒细胞和 单核细胞。小鼠将被用来检查羟基尿素的影响，这是 在预防急性冠脉综合征方面显示出治疗效果，与红细胞和 白细胞。目前使用镰状细胞病的小鼠模型 申请人可获得的，肺功能的体积描记测量 将补充结构的组织病理学研究。申请人 将延长研究，因为合作使其他小鼠在 项目的进程。佐治亚州-国立卫生研究院综合镰刀细胞中心 (共同赞助人詹姆斯·埃克曼)，亚特兰大弗吉尼亚州医疗机构的肺生物学小组 中心(共同发起人塞缪尔·阿瓜约)，内皮细胞活跃团体 佐治亚理工学院和埃默里大学的粘连，以及 莫尔豪斯医学院的微循环小组。假设： 表达人镰状血红蛋白的转基因小鼠比 正常小鼠因油酸注射致急性肺损伤 血细胞与内皮细胞的相互作用。具体目标是检查 不同血细胞在急性肺易感性增加中的作用 受伤。1.异常红细胞--(A)呈镰状，(B)黏附；2.中性粒细胞- (A)数量；(B)黏附/保持；(C)激活；3.单核细胞-(A) 数字，(B)粘连/固位，(C)激活；4.检查效果 羟基脲对急性肺损伤患者红细胞、中性粒细胞和单核细胞的影响。(完) 的摘要)

DESCRIPTION (Adapted from applicants' abstract) Overall objectives: Develop an animal model for the sickle acute chest syndrome (ACS), a life-threatening complication of human sickle cell disease, in order to study pathophysiology and test therapy. The applicant, who is trained in pediatric hematology-oncology, proposes to learn methods in pulmonary research and endothelial cell adhesion research under the mentorship of a pulmonologist and a hematologist. The study hypothesis is that pathophysiology of ACS includes erythrocyte (RBC) sickling and adhesion, neutrophils, and monocytes. Mice will be used to examine the effects of hydroxyurea, which has shown therapeutic benefit in preventing ACS, in relation to RBC and leukocytes. Using the murine models of sickle cell disease currently available to the applicant, plethysmographic measures of pulmonary function will complement the histopathologic studies of structure. The applicant will extend the studies as collaborations make other mice available during the course of the project. The Georgia-NIH Comprehensive Sickle Cell Center (co-sponsor James Eckman), the Lung Biology Group in Atlanta VA Medical Center (co-sponsor Samuel Aguayo), active groups in endothelial cell adhesions at Georgia Institute of Technology and Emory University, and microcirculation group at the Morehouse School of Medicine. Hypothesis: Transgenic mice expressing human sickle hemoglobin are more susceptible than normal mice to acute lung injury from oleic acid injection, due to abnormal interactions of blood cells and endothelium. Specific aims are to examine the roles of different blood cells in increased susceptibility to acute lung injury. 1. Abnormal RBC - (a) sickling, (b) adhesion; 2. Neutrophils - (a) numbers, (b) adhesion/retention, (c) activation; 3. Monocytes - (a) numbers, (b) adhesion/retention, (c) activation; 4. Examine effects hydroxyurea on RBC, neutrophils, and monocytes in acute lung injury. (End of Abstract)