STRUCTURAL BASIS OF CD28 REGULATION OF LUNG INFLAMMATION

CD28 调节肺部炎症的结构基础

• 批准号: 6629025
• 负责人: Jonathan M. Green
• 金额: $ 33.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629025
• 关键词: CD28 molecule; helper T lymphocyte; immunoregulation; inflammation; laboratory mouse; leukocyte activation /transformation; protein structure function; protein tyrosine kinase; respiratory hypersensitivity; tissue /cell culture

DESCRIPTION: (Adapted from the Applicant's Abstract): T lymphocytes are a major component of the inflammatory response and aberrant regulation of T cell activation and differentiation may be central to the pathogenesis of asthma. The CD28 co-stimulatory receptor is a critical regulator of T cell activation and differentiation, and thus may be an important target for therapy of immune mediated diseases. Manipulation of this receptor has been shown to alter the course of several animal models of disease, inducing models of antigen-induced airway inflammation. Accordingly, the primary goal of this proposal is to increase our understanding of the cellular and molecular basis by which CD28 modulates the T cell response to antigen. CD28 regulates multiple aspects of T cell functions, including proliferation, adhesion, T helper cell phenotype development and cell survival. The PI demonstrates that CD28 is essential for the development of antigen-induced inflammation in a murine model of airway disease. Sensitized CD28-deficient mice fail to develop airway inflammation or eosinophilia in response to antigen challenge. Examination of T helper cell phenotype in CD28 -/- mice demonstrates a defect in Th2 cytokine gene expression. The mechanism by which CD28 regulates these diverse aspects of T cell function is poorly understood, but likely involves multiple signaling pathways. Studies in transformed cell lines have implicated specific domains in the cytoplasmic trail of CD28 as important in signaling, but no consensus exists as to what is required for CD28 function in primary cells or in vivo responses. The data in primary T cells demonstrates a requirement for specific proline mediated interactions with the non-receptor tyrosine kinase lck in the regulation of T cell proliferation by CD28. The PI hypothesizes that multiple distinct structural domains of CD28 modulate specific features of T cell activation and differentiation. To address this, the following specific aims have been proposed: 1) determine the structural features of CD28 required for co-stimulation of primary T cells in vitro; and 2) characterize the specific cellular and molecular determinants by which CD28 regulates airway inflammation in vivo. These studies will provide critical data as to the regulation of T cell directed immune responses, and provide a rational basis for the development of new therapeutic strategies in the treatment of inflammatory lung disease.

描述：（改编自申请人的摘要）：T淋巴细胞是主要的 T细胞的炎症反应和异常调节的成分 激活和分化可能是哮喘发病机理的核心。 CD28共刺激受体是T细胞激活的关键调节剂 和分化，因此可能是治疗免疫的重要靶标 介导的疾病。该受体的操作已显示出改变 几种疾病动物模型的过程，诱导抗原诱导的模型 气道炎症。因此，该提议的主要目标是 提高我们对CD28的细胞和分子基础的理解 调节T细胞对抗原的反应。 CD28调节t的多个方面 细胞功能，包括增殖，粘附，T辅助细胞表型 发育和细胞存活。 PI证明CD28对于 在气道的鼠模型中，抗原引起的炎症的发展 疾病。敏化的CD28缺陷小鼠无法发展出气道炎症或 嗜酸性粒细胞响应抗原挑战。 T辅助细胞检查 CD28 - / - 小鼠中的表型显示了Th2细胞因子基因的缺陷 表达。 CD28调节T的机制 细胞功能知之甚少，但可能涉及多个信号 途径。转化的细胞系的研究已暗示了特定领域 CD28的细胞质轨迹在信号传导中很重要，但无共识 存在原代细胞或体内CD28功能所需的功能 回答。原代T细胞中的数据表明了对特定的要求 脯氨酸介导与非受体酪氨酸激酶LCK的相互作用 通过CD28调节T细胞增殖。 PI假设多个 CD28的不同结构域调节T细胞的特定特征 激活和分化。为了解决这个问题，以下具体目标 已经提出：1）确定CD28的结构特征 原代T细胞在体外的共同刺激； 2）特定特定 CD28调节气道炎症的细胞和分子决定因素 体内。这些研究将提供有关调节T的关键数据 细胞定向免疫反应，并为 开发新的治疗策略以治疗炎症性肺 疾病。