TRANSGENIC MOUSE MODEL FOR SICKLE ACUTE CHEST SYNDROME

描述 （改编自申请人摘要）总体目标：开发一种动物 镰状急性胸部综合征（ACS），一种危及生命的 人类镰状细胞病的并发症，以研究病理生理学 和测试疗法 申请人接受过儿科培训， 血液肿瘤学，建议学习肺部研究方法， 肺科医师指导下的内皮细胞粘附研究 和血液学家 研究假设ACS的病理生理学 包括红细胞（RBC）镰状化和粘附、中性粒细胞，以及 单核细胞 小鼠将被用来检查羟基脲的作用， 在预防ACS方面显示出治疗益处， 白细胞 使用目前镰状细胞病的小鼠模型， 申请人可用的肺功能体积描记测量 将补充结构的组织病理学研究。 申请人 将扩大研究，因为合作使其他小鼠在 项目的进程。 乔治亚-NIH综合镰状细胞中心 （共同赞助人James Eckman），亚特兰大VA医学中心肺生物学组 中心（共同申办者Samuel Aguayo），内皮细胞活性组 在格鲁吉亚理工学院和埃默里大学， 莫尔豪斯医学院的微循环小组。 假设： 表达人类镰状血红蛋白的转基因小鼠比 正常小鼠油酸注射致急性肺损伤，由于异常 血细胞和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损伤易感性增加中的作用 损伤 1. 异常红细胞-（a）镰状化，（B）粘附; 2. 中性粒细胞- (a)数量，（B）粘附/保持，（c）活化; 3. 单核细胞-（a） 数量，（B）粘附/保持，（c）活化; 4. 检查效果 在急性肺损伤中，羟基脲对红细胞、中性粒细胞和单核细胞影响。 （完 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)