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

描述(改编自《调查者摘要》)：炎症在 在心血管疾病中起重要作用，CD11/CD18整合素是 为开发新的治疗药物提供了有吸引力的目标。完成 抑制CD18，白细胞整合素的共同β链， 显著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(白细胞黏附缺陷型 我，小伙子i)。尽管遗传障碍LAD我提供了很大的洞察力 CD18家族的功能意义，CD18家族的相对贡献 在LAD I的表型异常中，每一个CD11整合素仍然存在 不清楚。选择性抑制特定的CD11整合素可能会有 在没有广泛应用的特定炎症条件下的治疗益处 寄主防御受损。为了评估每个CD11的功能 整合素，小鼠将被用于两个一般的实验范例： 首先，评估失去一个CD11的功能后果 第二，评估单个CD11保留的功能 整合素存在。具体目标是：1.培育具有特定功能的小鼠 CD11整合素的每一个缺陷和重要的组合突变 胚胎干细胞中的定向同源重组。老鼠已经 已开发出CD11a、CD11b和CD11c缺乏的病毒。为了 更好地确定CD11整合素在PMN功能中的作用 建议将CD11a+CD11b、CD11b+CD11c和 CD11a+CD11c，其中只有一个CD11链存在于小鼠PMN上， 缺乏CD11d。2.描述由于选择性疾病引起的表型变化 CD11整合素在中性粒细胞功能方面的缺陷。一个 结合体外和体内研究将提供新的信息 单个CD11整合素在迁移、黏附、 脱颗粒、过氧化氢的产生和细胞信号传递，包括 与Fc受体的相互作用。3.描述每个人的贡献 CD11整合素对宿主对常见细菌和真菌病原体的反应 体外和体内。

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.