Regulation of Mucosal Lymphocytes

粘膜淋巴细胞的调节

• 批准号: 7917834
• 负责人: Richard S Blumberg
• 金额: $ 12.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917834
• 关键词: Affinity; Alternative Splicing; Animal Model; Antibodies; Antigens; Applications Grants; B-Lymphocytes; Binding; CD28 gene; CD3 Antigens; Calmodulin 1; Carcinoembryonic Antigen; Cell Adhesion Molecules; Cell Count; Cell Line; Cell physiology; Cell surface; Cells; Cytoplasmic Tail; Development; Disease; Down-Regulation; Equilibrium; Exons; Exposure to; Generations; Grant; Gut associated lymphoid tissue; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Ligands; Ligation; Logic; Lymphocyte; Major Histocompatibility Complex; Mediator of activation protein; Molecular; Mus; Pathogenesis; Physiological; Property; Protein Isoforms; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Site; Synapses; System; T cell regulation; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Technology; Tissues; Transfection; Transgenic Animals; Transgenic Organisms; assault; carcinoembryonic antigen-related cell adhesion molecules; cell type; cytokine; in vivo; knock-down; novel; pathogen; receptor; response; retroviral-mediated; therapeutic target

DESCRIPTION (provided by applicant): The gut-associated lymphoid tissue must manage a tedious balance between "physiologic" and "tissue destructive" inflammation associated acutely with exposure to pathogens and other exogenous assaults and chronically in the setting of the idiopathic types of inflammation associated with inflammatory bowel disease (IBD). At the center of this dysregulated inflammation is the T cell and its activity levels, which are responsible for the excess quantities of cytokines and other mediators responsible for the inflammation. Understanding the mechanisms of T cell activation and downregulation are thus critical to gaining an understanding of IBD and the potential to therapeutically manipulate intestinal inflammation. T cells are primarily activated by signals delivered to the antigen-specific receptor, the T cell receptor (TCR)/CD3 complex, which is modified by secondary signals that are either co-stimulatory or co-inhibitory. The responsiveness of T cells are tunable through the specific affinities of its TCR/CD3 complex to antigen in the context of major histocompatibility complex (MHC) proteins and the compilation of the concomitant positive or negative co-stimulatory and co-inhibitory signals, respectively. The major secondary co-stimulatory and co-inhibitory signals for the majority of T cells are those delivered by either CD28 or CTLA-4, respectively. It has, however, been increasingly evident that many T cells, including those in the intestine, do not express these molecules and, as a corollary, other molecules may provide such functions. This grant proposes to investigate the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as a co-inhibitory or co-stimulatory molecule through the generation of distinct CEACAM1 isoforms that possess a long or short cytoplasmic tail, respectively, which are generated by alternate splicing. We, therefore, propose the following specific aims: (1) Define CEACAM1 expressing a long (L) cytoplasmic tail as a co-inhibitory molecule on T cells by the development of an animal model that knocks-down CEACAM1 expression specifically in T cells and define the molecular mechanisms by which this inhibition occurs both in terms of the ligand involved and the intracellular signaling pathways; (2) determine whether CEACAM1 isoforms expressing a short (S) cytoplasmic tail are co-stimulatory of TCR/CD3 complex signaling and the development of intestinal inflammation through the generation of transgenic animals that over-express these forms and the characterization of CEACAM1-L and -S expression in T cells during T cell activation, and; (3) determine whether CEACAM1 on T cells can function in the negative regulation of other cell types and their implications for contact-dependent T and B cell regulation. These studies will determine whether CEACAM1 is a novel non-CD28-related molecule that can regulate T cells and act as a therapeutic target for inflammatory conditions such as IBD.

描述（由申请人提供）：肠道相关淋巴组织必须在“生理性”和“组织破坏性”炎症之间保持繁琐的平衡，这些炎症与暴露于病原体和其他外源性攻击密切相关，并且长期与相关的特发性炎症类型相关。患有炎症性肠病（IBD）。这种失调性炎症的核心是 T 细胞及其活性水平，它们是导致炎症的细胞因子和其他介质过量的原因。因此，了解 T 细胞激活和下调的机制对于了解 IBD 以及治疗控制肠道炎症的潜力至关重要。 T 细胞主要由传递到抗原特异性受体（T 细胞受体 (TCR)/CD3 复合物）的信号激活，该复合物由共刺激或共抑制的次级信号修饰。 T 细胞的反应性可通过其 TCR/CD3 复合物在主要组织相容性复合体 (MHC) 蛋白背景下与抗原的特异性亲和力以及分别伴随的正或负共刺激和共抑制信号的汇编来调节。大多数 T 细胞的主要次级共刺激和共抑制信号分别由 CD28 或 CTLA-4 传递。然而，越来越明显的是，许多 T 细胞，包括肠道中的 T 细胞，不表达这些分子，因此，其他分子可能提供此类功能。该资助计划通过生成分别具有长或短胞质尾的不同 CEACAM1 亚型来研究癌胚抗原相关细胞粘附分子 1 (CEACAM1) 作为共抑制或共刺激分子的作用。通过交替拼接。因此，我们提出以下具体目标：（1）通过开发特异性敲低 T 细胞中 CEACAM1 表达的动物模型，将表达长（L）胞质尾的 CEACAM1 定义为 T 细胞的共抑制分子，并定义这种抑制在涉及的配体和细胞内信号通路方面发生的分子机制； (2) 通过产生过度表达这些形式的转基因动物和 CEACAM1-L 的表征，确定表达短 (S) 胞质尾的 CEACAM1 亚型是否共同刺激 TCR/CD3 复合物信号传导和肠道炎症的发展T细胞激活过程中T细胞中的-S表达，以及； (3)确定T细胞上的CEACAM1是否可以在其他细胞类型的负调节中发挥作用及其对接触依赖性T和B细胞调节的影响。这些研究将确定 CEACAM1 是否是一种新型非 CD28 相关分子，可以调节 T 细胞并作为 IBD 等炎症性疾病的治疗靶点。