MAC 1/LFA 1/P150 95 AND PMN LEUKOCYTE FUNCTION

MAC 1/LFA 1/P150 95 和 PMN 白细胞功能

基本信息

批准号：
6537536
负责人：
CHRISTIE Mitchell BALLANTYNE
金额：
$ 36.15万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2004-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6537536
关键词：
CD antigens antibody receptor biological signal transduction cell adhesion cell cell interaction cell migration gene mutation genetically modified animals hydrogen peroxide inflammation integrins laboratory mouse leukocyte activation /transformation leukocyte adhesion molecules leukocytes neutrophil protein structure function

项目摘要

DESCRIPTION (Adapted from Investigator's Abstract): Inflammation plays an important role in cardiovascular disease, and the CD11/CD18 integrins are attractive targets for the development of new therapeutic agents. Complete inhibition of CD18, the common beta chain of the leukocyte integrins, profoundly reduces emigration of neutrophils (PMN) at sites of inflammation and leads to a severe immunodeficiency syndrome (leukocyte adhesion deficiency type I, LAD I). Although the genetic disorder LAD I has provided great insight into the functional significance of the CD18 family, the relative contributions of each of the CD11 integrins in the phenotypic abnormalities seen in LAD I remain unclear. Selective inhibition of specific CD11 integrins could potentially have therapeutic benefit in specific inflammatory conditions without broad impairment of host defense. In an effort to evaluate the function of each CD11 integrin, mice will be generated for use in two general experimental paradigms: First, to assess the functional consequences of the loss of a single CD11 integrin, and second, to assess the functions retained when a single CD11 integrin is present. The specific aims are: 1. Develop mice with specific deficiencies in each of the CD11 integrins and important combined mutations by targeted homologous recombination in embryonic stem cells. Mice have already been developed that are deficient in CD11a, CD11b, and CD11c. In order to better define the role of CD11 integrins in PMN function, the investigator proposes to make the double knockouts of CD11a + CD11b, CD11b + CD11c, and CD11a + CD11c, in which only a single CD11 chain is present on murine PMN, which lack CD11d. 2. Characterize the phenotypic changes due to selective deficiencies of the CD11 integrins with respect to neutrophil function. A combination of in vitro and in vivo studies will provide novel information on the functions of individual CD11 integrins in migration, adhesion, degranulation, hydrogen peroxide production, and cellular signaling, including interactions with the Fc receptors. 3. Characterize the contribution of each CD11 integrin on the host response to common bacterial and fungal pathogens in vitro and in vivo.

描述（根据调查员的摘要改编）：发炎发挥在心血管疾病和CD11/CD18整合素中的重要作用是开发新治疗剂的有吸引力的目标。完全的 CD18的抑制作用，白细胞整合蛋白的常见β链，严重减少炎症部位中性粒细胞（PMN）的迁移导致严重的免疫缺陷综合征（白细胞粘附缺乏类型我，我）。尽管我为遗传疾病小伙子提供了深入的了解 CD18家族的功能意义，是在LAD中看到的表型异常中的每一个CD11整合素不清楚。选择性抑制特定CD11整合素可能具有在没有广泛的特定炎症条件下的治疗益处宿主防御的损害。为了评估每个CD11的功能整合素，将生成两个一般实验范式中的小鼠：首先，评估单个CD11丢失的功能后果整合素，其次是评估单个CD11时保留的功能整联蛋白存在。具体目的是：1。开发特定的小鼠每种CD11整联蛋白的缺陷和重要的合并突变。胚胎干细胞中的靶向同源重组。老鼠已经已经开发出缺乏CD11a，CD11b和CD11C的开发。为了更好地定义了CD11整合素在PMN功能中的作用，研究者建议将CD11A + CD11b，CD11b + CD11C的双重敲除和 CD11A + CD11C，其中仅在鼠PMN上存在一个CD11链，缺少CD11D。 2。表征由于选择性而引起的表型变化 CD11整联蛋白相对于中性粒细胞功能的缺乏。一个体外研究和体内研究的结合将提供有关有关的新信息单个CD11整联蛋白在迁移，粘附中的功能，脱粒，过氧化氢的产生和细胞信号传导，包括与FC受体的相互作用。 3。表征每个的贡献 CD11整联蛋白在宿主对常见细菌和真菌病原体的反应上体内和体内。