L-ARGININE AVAILABILITY REGULATES PROLIFERATION OF MALIGNANT T-CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肿瘤通过多种机制抑制T细胞增殖，包括髓系抑制细胞产生的精氨酸酶I耗竭非必需氨基酸L-精氨酸(L-Arg)。我们的初步数据显示，精氨酸酶I耗尽L-精氨酸会损害原代T细胞的增殖，并发现它特异性地抑制细胞周期蛋白D3的表达，使T细胞滞留在细胞周期的G0-G1期。因此，我们认为精氨酸酶也可能是治疗T细胞恶性肿瘤的重要药物。在这个方案中，我们将研究L-精氨酸饥饿损害恶性T细胞增殖的机制，并测试精氨酸酶注射是否可以在体内用于T细胞白血病的治疗。我们的假设是，精氨酸酶I饥饿L-精氨酸可以通过抑制细胞周期相关蛋白的表达来阻止恶性T细胞的增殖，因此可以用于T细胞增生性疾病的治疗，如T细胞白血病。为了验证这一假设，我们提出了以下具体目标： 1.探讨L-精氨酸饥饿损伤恶性T细胞体外增殖的分子机制。 2.在T细胞白血病模型中验证精氨酸酶I注射液降低L-精氨酸水平和阻断细胞周期蛋白D3表达的预测。 3.确定恶性T细胞中GCN2蛋白的激活是否是启动L-精氨酸饥饿引起的转录后和翻译后改变的主要检验点。 4.检测针对GCN2通路的治疗是否在T细胞恶性肿瘤中产生抗肿瘤作用。 5.在注射免疫缺陷小鼠的T-ALL患者的样本中，检验精氨酸酶处理诱导抗肿瘤效应的预测。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tumors inhibit T cell proliferation through several mechanisms, including the depletion of the non-essential amino acid L-Arginine (L-Arg) by arginase I produced in myeloid derived suppressor cells (MDSC). Our preliminary data show that L-Arg depletion by arginase I impairs primary T cell proliferation and found that it specifically inhibits the expression of cyclin D3, arresting T cells in G0-G1 phase of the cell cycle. We therefore propose that arginase may also be an important therapeutic agent in T cell malignancies. In this proposal we will study the mechanisms by which L-Arg starvation impairs proliferation of malignant T cells and test whether arginase injection can be used in vivo for the treatment of T cell leukemias. Our hypothesis is that L-Arg starvation by arginase I blocks malignant T cell proliferation by inhibiting the expression of cell cycle associated proteins and can therefore be used in the treatment of T cell proliferate disorders such as T cell leukemia. To test this hypothesis, we propose the following specific aims: 1. To characterize the molecular mechanisms by which L-Arginine starvation impairs malignant T cell proliferation in vitro. 2. To test the prediction that arginase I injection will decrease L-Arginine levels and block cyclin D3 expression in vivo in a T cell leukemia model. 3. To determine whether GCN2 kinase activation in malignant T cells is the major check point that initiates the post-transcriptional and translational changes induced by L-Arginine starvation. 4. To test whether therapies targeting GCN2 pathway induce an anti-tumoral effect in T cell malignancies. 5. Test the prediction that arginase treatment induces an anti-tumoral effect in samples from T-ALL patients injected into immunodeficient mice.