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）：淋巴细胞稳态需要对坐标进行信号级联的调节，以控制增殖，分化和死亡。 这些过程的失调是发展淋巴恶性肿瘤的必要前提。 我们的实验室最近报道了一种新型鼠模型，该模型包含一个突变，该突变破坏了二聚过程中受体样蛋白酪氨酸磷酸酶CD45的负调节。 这些小鼠伴有T和B细胞多克隆激活，大量的脾肿大和早死亡的多克隆活化，发展出深刻的淋巴增生性疾病。 一个子集还形成自身免疫性的污名，包括抗双链DNA抗体形成和免疫复合物介导的肾小球肾炎。 为了定义负责疾病产生的细胞类型，CD45突变小鼠与缺乏T，B或T和B细胞的小鼠配对。 遗传消除B细胞，但没有T细胞导致自身免疫和淋巴增生性疾病消融。 相反，缺乏T细胞导致淋巴瘤患病率显着增加。 这些观察结果支持以下假设：通过二聚化对CD45功能的精确调节对于维持造血系统内稳态至关重要。 该功能的破坏可能会产生深远的后果，从而导致淋巴增长，自身免疫性和恶性肿瘤。 该提案的目的是定义稳态分解的分子和细胞基础，并确定淋巴瘤发展所需的步骤。 第一个目的测试了有助于疾病开始的B细胞中性机制。 第二个目标的重点是微环境的贡献，该贡献可能增强B细胞膨胀以及T细胞抑制淋巴细胞促发生的机制。 在第三个目标中，使用生化和基因表达分析来解决CD45突变有助于疾病的分子基础。 阵列CGH和ENU诱变用于开始确定有助于从高增殖到恶性状态的合作事件。 这些研究应提供有关免疫调节，自身免疫性和淋巴恶性肿瘤之间联系的重要见解，并提高我们对管理免疫监测机制的理解。