Role of Tcl-1 in Lymphoid Development

Tcl-1 在淋巴发育中的作用

• 批准号: 6232701
• 负责人: JAY L ROTHSTEIN
• 金额: $ 25.85万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-27 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6232701
• 关键词: RNase protection assay; T lymphocyte; animal breeding; ataxia telangiectasia; cell line; cell proliferation; chronic lymphocytic leukemia; comorbidity; developmental genetics; disease /disorder model; embryogenesis; gene expression; genetic strain; genetically modified animals; immunocytochemistry; laboratory mouse; model design /development; mutant; neoplasm /cancer genetics; oncogenes

In leukemias, non-random chromosomal translocations have been determined to predispose or cause changes in cell growth and/or survival that promote malignancy. The detailed study of the mechanisms of human cancer causing genes and their protein structure requires the identification or development of animal models to allow the study of protein function. Patients with the disease ataxia telangiectasia (AT) frequently suffer from T cell chromic lymphocytic leukemia (T-CLL) carrying a 14q32.1-q11 inversion/translocation. The chromosomal breakpoint gene Tcll and the related MTCP1 genes have been recently cloned and characterized and the gene responsible for their underlying disease (ATM) has been cloned and a null mutation produced in mice (Atm-/-). We hypothesize that Tcll plays a critical role in the development of cancer. Further the use of the newly isolated murine Tcll gene for the development of a mouse model of lymphoproliferation will provide an ideal opportunity to study the Tcll protein and its role in inducing mature T cell lymphoproliferations that lead to CLL. Consequently, we propose three experimental aims: 1 Evaluate the expression of Tcll during murine embyrogenesis. The spatial expression of Tcll will be critical for null mutant analysis and functional studies. 2 Develop and analyze Tcll transgenic and Tcll -/- null mutant mice. These strains will be required for the full development of an animal model of human disease. 3 Establish a mammalian model of T cell lymphoproliferation and CLL. Tcll -/- mutant mice will be bred with other mouse strains, such as the Atm +/- mice to recapitulate human CLL. We expect that through the development of these molecular tools, including a murine model of CLL, therapies for the human disease can be developed and tested.

在白血病中，非随机染色体易位已被确定会诱发或引起细胞生长和/或存活的变化，从而促进恶性肿瘤。对人类致癌基因及其蛋白质结构机制的详细研究需要鉴定或开发动物模型以允许研究蛋白质功能。共济失调性毛细血管扩张症 (AT) 患者经常患有携带 14q32.1-q11 倒位/易位的 T 细胞铬淋巴细胞白血病 (T-CLL)。染色体断点基因 Tcll 和相关的 MTCP1 基因最近已被克隆和表征，导致其潜在疾病 (ATM) 的基因也已被克隆，并在小鼠中产生了无效突变 (Atm-/-)。我们假设 Tcll 在癌症的发展中发挥着关键作用。此外，使用新分离的鼠 Tcll 基因开发小鼠淋巴增殖模型将为研究 Tcll 蛋白及其在诱导成熟 T 细胞淋巴增殖（导致 CLL）中的作用提供理想的机会。因此，我们提出三个实验目标： 1 评估小鼠胚胎发生过程中 Tcll 的表达。 Tcll 的空间表达对于无效突变分析和功能研究至关重要。 2 开发并分析 Tcll 转基因小鼠和 Tcll -/- 无效突变小鼠。这些菌株对于人类疾病动物模型的全面开发是必需的。 3 建立哺乳动物T细胞淋巴增殖和CLL模型。 Tcll -/- 突变小鼠将与其他小鼠品系（例如 Atm +/- 小鼠）一起繁殖，以重现人类 CLL。我们期望通过开发这些分子工具（包括 CLL 小鼠模型），可以开发和测试人类疾病的疗法。