ROLE FOR THE ECTOENZYME CD38 IN IMMUNE RESPONSES

胞外酶 CD38 在免疫反应中的作用

• 批准号: 2848944
• 负责人: Frances E. Lund
• 金额: $ 22.96万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2848944
• 关键词: B cell receptor; B lymphocyte; CD38 molecule; Streptococcus; T lymphocyte; antibody formation; bactericidal immunity; biological signal transduction; bone marrow; enzyme activity; gene expression; gene mutation; gene targeting; genetically modified animals; humoral immunity; immunoregulation; laboratory mouse; protein structure function; tissue mosaicism

DESCRIPTION (Adapted from Investigator's Abstract): The innate and adaptive arms of the immune system regulate the clearance of infectious organisms by effector mechanisms induced through a complex set of receptor/ligand interactions between a number of different cell types. The molecular mechanism by which most receptors induce their biologic effects is through a process of receptor aggregation and subsequent activation of intracellular enzymes, such as protein kinases, that are associated with the cytoplasmic tails of the receptors. The activation of these enzymes in turn initiate signaling cascades that regulate cellular activation, proliferation, differentiation, and effector function. However, there are a number of receptors that cannot directly activate the intracellular signal transduction machinery, yet are capable of modulating cellular responses. Interestingly, many of these unusual receptors have ecto-enzymatic properties and can be organized into extracellular metabolic pathways such that the product of one ecto- enzymatic reaction serves as the substrate for the next reaction. One example of such an ecto-enzyme is the NAD glycohydrolase, CD38. CD38 utilizes the dinucleotide, NAD, as a substrate and catalyzes the production of several metabolites that can be directly utilized by cells, used as agonists for other signaling receptors, or utilized by other extracellular enzymes to generate additional metabolites. In addition to its enzymatic properties, CD38 has also has been shown to regulate a number of functions in vitro including lymphocyte adhesion, activation, proliferation, apoptosis, and effector function. CD38 plays an important role in vivo as well, since mice that are genetically deficient for CD38 cannot mount a protective response to bacterial pathogens such as Streptococcus pneumoniae. In addition, CD38-deficient animals make poor primary humoral immune response to experimental antigens and are unable to mount a productive humoral memory response. Although CD38 clearly regulates both innate and acquired immune responses, the molecular mechanism by which CD38 or other ecto-enzymes modulate immune responses is unknown. Therefore, the goal of this proposal is to identify the cellular and molecular mechanisms by which CD38 regulates the immune response to foreign antigens. The specific aims are designed to test the hypothesis that the extracellular enzymatic activity of CD38 is required for the generation of productive humoral and innate immune responses. These experiments will provide a framework for understanding the elusive role of ecto-enzymes such as CD38 in the generation and maintenance of protective immunity.

描述（根据调查员的摘要改编）：先天和 免疫系统的自适应臂调节感染性的清除 通过效应器机制通过一组复杂的一组诱导的生物体 许多不同细胞类型之间的受体/配体相互作用。 大多数受体诱导其生物学的分子机制 效果是通过受体聚集和随后的过程 细胞内酶的激活，例如蛋白激酶，是 与受体的细胞质尾巴相关。激活 这些酶依次启动调节的信号级联 细胞激活，增殖，分化和效应子 功能。但是，有许多无法直接的受体 激活细胞内信号转导机械，但 能够调节细胞反应。有趣的是，其中许多 异常的受体具有外酶特性，可以组织 进入细胞外代谢途径，使一个ecto-的乘积 酶促反应是下一个反应的底物。一 这种外酶的示例是NAD糖醇，CD38。 CD38 利用二核苷酸NAD作为底物，并催化 生产几种可以直接利用的代谢产物 细胞，用作其他信号受体的激动剂，或用 其他细胞外酶产生其他代谢产物。在 除了其酶特性外，CD38也已显示为 在体外调节许多功能，包括淋巴细胞粘附， 激活，增殖，凋亡和效应子功能。 CD38播放 在体内也是一个重要的作用，因为遗传上的小鼠 缺乏CD38无法对细菌产生保护性反应 病原体，例如肺炎链球菌。另外，CD38缺陷 动物使原发性不良对实验的免疫反应 抗原，无法安装富有生产力的体液记忆响应。 尽管CD38显然调节了先天和获得的免疫 响应，CD38或其他异位酶的分子机制 调节免疫反应尚不清楚。因此，目标的目标 建议是确定细胞和分子机制 CD38调节对外国抗原的免疫反应。具体 目的旨在检验细胞外的假设 CD38的酶活性是生成生产性需要的 体液和先天免疫反应。这些实验将提供 理解ecto-酶的难以捉摸的框架，例如 CD38在保护和维持保护性免疫中。