L-ARGININE AVAILABILITY REGULATES PROLIFERATION OF MALIGNANT T-CELLS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肿瘤通过几种机制抑制T细胞增殖，包括髓源性抑制细胞（MDSC）中产生的脱氢酶I消耗非必需氨基酸L-精氨酸（L-Arg）。我们的初步数据表明，L-Arg耗尽由辅酶I损害原代T细胞增殖，并发现它特异性地抑制细胞周期蛋白D3的表达，阻止T细胞在细胞周期的G 0-G1期。因此，我们建议，β-内酰胺酶也可能是一个重要的治疗剂在T细胞恶性肿瘤。在这个建议中，我们将研究L-Arg饥饿损害恶性T细胞增殖的机制，并测试是否可以在体内用于治疗T细胞白血病。我们的假设是，L-Arg饥饿通过抑制细胞周期相关蛋白的表达阻断恶性T细胞增殖，因此可以用于治疗T细胞增殖障碍，如T细胞白血病。为了检验这一假设，我们提出了以下具体目标： 1. 研究精氨酸饥饿对体外恶性T细胞增殖影响的分子机制。 2. 在T细胞白血病模型中，检测体内注射精氨酸酶I将降低L-精氨酸水平并阻断细胞周期蛋白D3表达的预测。 3. 确定恶性T细胞中GCN 2激酶激活是否是启动L-精氨酸饥饿诱导的转录后和翻译变化的主要检查点。 4. 测试靶向GCN 2通路的疗法是否在T细胞恶性肿瘤中诱导抗肿瘤作用。

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 shows 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.