Role of CD45 in Hematopoiesis and Lymphomagenesis

CD45 在造血和淋巴瘤发生中的作用

• 批准号: 6918088
• 负责人: Michelle L. Hermiston
• 金额: $ 12.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918088
• 关键词: B lymphocyte; CD antigens; T lymphocyte; biological signal transduction; carcinogenesis; cell cell interaction; cell growth regulation; cell proliferation; comparative genomic hybridization; gene expression; genetic manipulation; genetically modified animals; hematopoiesis; laboratory mouse; leukocyte activation /transformation; lymphoma; microarray technology; neoplasm /cancer genetics; protein tyrosine phosphatase

DESCRIPTION (provided by applicant): Lymphocyte homeostasis requires the coordinate regulation of signaling cascades governing proliferation, differentiation, and death. Dysregulation of these processes is a necessary prerequisite for the development of lymphoid malignancies. Our lab recently reported a novel murine model containing a mutation that disrupts the negative regulation of the receptor-like protein tyrosine phosphatase CD45 during dimerization. These mice develop a profound lymphoproliferative disorder with polyclonal activation of T and B cells, massive splenomegaly, and premature death. A subset also develops stigmata of autoimmunity including anti-double stranded DNA antibody formation and immune complex-mediated glomerulonephritis. To define the cell type responsible for disease generation, the CD45 mutant mice were mated to mice deficient in T, B, or T and B cells. Genetic elimination of B cells, but not T cells results in ablation of the autoimmune and lymphoproliferative disorders. In contrast, absence of T cells resulted in a dramatic increase in the prevalence of lymphoma. These observations support the hypothesis that precise regulation of CD45 function by dimerization is essential for the maintenance of homeostasis within the hematopoietic system. Disruption of this function can have profound consequences leading to lymphoproliferation, autoimmunity, and malignancy. The goal of this proposal is to define the molecular and cellular basis for the breakdown of homeostasis and to identify the steps required for the development of lymphomas. The first aim tests B cell-intrinsic mechanisms that contribute to disease initiation. The second aim focuses on contributions from the microenvironment that may enhance B cell expansion and the mechanisms by which T cells inhibit lymphomagenesis. In the third aim, biochemical and gene expression analyses are used to address the molecular basis by which the CD45 mutation contributes to disease. Array CGH and ENU mutagenesis are used to begin to identify cooperating events that contribute to the progression from hyperproliferating to malignant state. These studies should provide important insights into the links between immune regulation, autoimmunity, and lymphoid malignancies as well as improve our understanding of the mechanisms governing immune surveillance.

描述（由申请人提供）：淋巴细胞稳态需要控制增殖、分化和死亡的信号级联的协调调节。 这些过程的失调是淋巴恶性肿瘤发生的必要先决条件。 我们的实验室最近报道了一种新型小鼠模型，该模型含有一种突变，该突变会破坏受体样蛋白酪氨酸磷酸酶 CD45 在二聚化过程中的负调节。 这些小鼠出现严重的淋巴增殖性疾病，伴有 T 细胞和 B 细胞的多克隆激活、脾脏肿大和过早死亡。 一部分还出现自身免疫的症状，包括抗双链 DNA 抗体形成和免疫复合物介导的肾小球肾炎。 为了确定导致疾病产生的细胞类型，将 CD45 突变小鼠与缺乏 T、B 或 T 和 B 细胞的小鼠交配。 B 细胞（而非 T 细胞）的基因消除可消除自身免疫性疾病和淋巴增殖性疾病。 相比之下，T细胞的缺失导致淋巴瘤患病率急剧增加。 这些观察结果支持这样的假设：通过二聚化精确调节 CD45 功能对于维持造血系统内的稳态至关重要。 这种功能的破坏可能会产生深远的后果，导致淋巴细胞增殖、自身免疫和恶性肿瘤。 该提案的目标是定义稳态破坏的分子和细胞基础，并确定淋巴瘤发展所需的步骤。 第一个目标是测试导致疾病发生的 B 细胞内在机制。 第二个目标侧重于可能增强 B 细胞扩增的微环境的贡献以及 T 细胞抑制淋巴瘤发生的机制。 第三个目标是利用生化和基因表达分析来解决 CD45 突变导致疾病的分子基础。 阵列 CGH 和 ENU 诱变用于开始识别有助于从过度增殖到恶性状态进展的协同事件。 这些研究应该为免疫调节、自身免疫和淋巴恶性肿瘤之间的联系提供重要的见解，并提高我们对免疫监视机制的理解。