MS4A Family Members in Health and Disease

MS4A 健康和疾病家族成员

• 批准号: 7105656
• 负责人: THOMAS F TEDDER
• 金额: $ 24.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105656
• 关键词: B lymphocyte; autoimmune disorder; autoimmunity; biological signal transduction; clinical research; gene expression; human tissue; humoral immunity; laboratory mouse; leukemia; lymphoma; monoclonal antibody; neoplasm /cancer immunotherapy; phosphorylation

DESCRIPTION (provided by applicant): B lymphocytes are the central mediators of humoral immunity. Aberrant B cell function contributes to many autoimmune diseases and age-related defects in humoral immunity, with malignant B cells representing the primary cell type in leukemia and lymphoma. B cell function is regulated by cell-surface molecules that generate transmembrane signals, regulate intercellular communication, and direct lymphocyte development. The aim of these studies is to examine the in vivo function of CD20, a B cell-specific cell-surface protein, and other members of the MS4A gene family that we have recently identified. CD20 is a membrane embedded component of an oligomeric complex that regulates transmembrane Ca2+ transport and cell cycle progression. Anti-CD20 immunotherapy has become a standard treatment for non-Hodgkin's lymphoma, and shows great promise for the treatment of autoimmunity. Despite this, relatively little is known about the function of CD20 in vivo and why it is such an effective target for immunotherapy. Since mechanistic and outcome studies are difficult and expensive in humans and other primates, we have developed mouse models for anti-CD20 mAb therapy that allows us to determine the molecular basis for therapeutic efficacy in vivo. We hypothesize that the molecular structure and function of CD20 and other MS4A family members makes them unique targets for effective therapy. To test this hypothesis, we will determine how CD20-directed therapies regulate B cell function in vivo and determine whether other members of the MS4A gene family are also effective immunotherapy targets. In Specific Aim 1, the functional significance and consequences of anti-CD20 mAb therapy will be assessed in normal mice. In Specific Aim 2, the molecular and cellular basis for B cell clearance will be determined. In Specific Aim 3, the efficacy and mechanism of mAb therapy will be assessed in mouse models of lymphoma. Specific Aim 4 will focus on the structure and expression of 20 newly-identified members of the MS4A gene family in mouse and man to determine whether they are appropriate targets for immunotherapy. Since CD20 provides an important regulatory checkpoint for ablating or adjusting B cell development and function, a molecular understanding of how it and other MS4A family members function will provide new avenues for modulating humoral immunity and effectively treating human disease.

描述（由申请人提供）：B淋巴细胞是体液免疫的中枢介质。异常的B细胞功能导致许多自身免疫性疾病和体液免疫中与年龄相关的缺陷，恶性B细胞是白血病和淋巴瘤的主要细胞类型。B细胞的功能受细胞表面分子的调控，这些分子产生跨膜信号，调节细胞间通讯，并指导淋巴细胞的发育。这些研究的目的是检查CD20（一种B细胞特异性细胞表面蛋白）和我们最近发现的MS4A基因家族的其他成员的体内功能。CD20是一种低聚复合物的膜嵌入成分，调节跨膜Ca2+运输和细胞周期进程。抗cd20免疫疗法已成为非霍奇金淋巴瘤的标准治疗方法，并在治疗自身免疫方面显示出巨大的希望。尽管如此，人们对这一现象所知相对较少