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

MAC 1/LFA 1/P150 95 和 PMN 白细胞功能

• 批准号: 6184621
• 负责人: CHRISTIE Mitchell BALLANTYNE
• 金额: $ 31.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184621
• 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

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（改编自研究者摘要）：炎症在 在心血管疾病中起重要作用，CD 11/CD 18整合素是 这是开发新治疗剂的有吸引力的靶点。完成 抑制CD 18，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（白细胞粘附缺陷型 I，LAD I）。虽然遗传性疾病LAD I已经为我们提供了很好的见解， CD 18家族的功能意义， 在LAD I中观察到的表型异常中的每种CD 11整合素仍然存在， 不清楚特异性CD 11整合素的选择性抑制可能具有 在特定炎症性疾病中的治疗益处， 破坏宿主防御。为了评估每个CD 11的功能， 将产生用于两种一般实验范例的小鼠： 首先，评估单个CD 11缺失的功能后果， 整合素，第二，评估当单个CD 11 存在整联蛋白。具体目标是：1.使小鼠具有特定的 CD 11整合素中的每一种的缺陷和重要的组合突变， 胚胎干细胞中的靶向同源重组。老鼠已经 已经开发出缺乏CD 11 a、CD 11b和CD 11 c的细胞。为了 为了更好地确定CD 11整合素在PMN功能中的作用，研究者 提出进行CD 11 a + CD 11b、CD 11b + CD 11 c和CD 11b + CD 11 c的双敲除， CD 11 a + CD 11 c，其中鼠PMN上仅存在单个CD 11链， 缺乏CD 11 d。2.描述由于选择性 CD 11整合素在中性粒细胞功能方面的缺陷。一 体外和体内研究的结合将提供关于 单个CD 11整联蛋白在迁移，粘附， 脱粒、过氧化氢产生和细胞信号传导，包括 与Fc受体的相互作用。3.描述每个人的贡献 CD 11整合素对常见细菌和真菌病原体宿主反应的影响 体外和体内。