PKC Theta--A Novel Drug Target in T Cell Leukemias

本研究的目的是验证蛋白激酶C-theta （PKC- theta）作为PKC家族的一员，在T细胞中选择性表达，在成熟T细胞活化中起重要作用，作为治疗干预人类T细胞白血病的药物靶点。这一建议源于我们最近对人类T细胞白血病的发现。这一建议源于我们最近的发现，PKC-theta保护几种类型的恶性或活化的T细胞免受fas或uv诱导的凋亡。在这里，我们提出旨在扩展和进一步验证这些发现的研究。Aim 1旨在建立白血病T细胞存活或生长与PKC-theta之间的因果关系。我们将分析PKC-theta在几种人类建立的T细胞白血病和小鼠T细胞淋巴瘤（EL4）中的表达、细胞内定位和催化活性，以确定这些细胞的存活或生长是否与组成型PKC-theta激活有关。然后，我们将确定旨在选择性抑制PKC-theta功能的实验策略是否与诱导凋亡方案协同作用，以促进这些细胞的凋亡。相反，我们将确定组成型活性PKC-theta是否增加了对细胞凋亡的抗性。在Aim 2中，我们将把类似的分析扩展到几种T细胞白血病小鼠体内模型，以确定选择性PKC-theta抑制药物或遗传策略是否抑制小鼠T细胞白血病的生长，或者相反，活性PKC-theta转基因是否促进肿瘤生长。这些研究可能会确立PKC-theta在介导T细胞白血病生长的生存信号中的选择性作用，并验证这种T细胞选择性酶作为治疗药物靶点。结合几家制药公司正在努力开发选择性PKC-theta抑制剂和可用的高通量筛选分析，拟议的研究可能为T细胞白血病提供一种新的治疗策略。

The objective of this proposal is to validate protein kinase C-theta (PKC- theta, a member of the PKC family, which is selectively expressed in T cells and plays an important role in mature T cell activation, as a drug target for therapeutic intervention with human T cell leukemias. This proposal derives from our recent finding with human T cell leukemias. This proposal derives from our recent finding that PKC-theta protects several types of malignant or activated T cells from Fas-or UV-induced apoptosis. Here we propose studies aimed at extending and further validating these findings. Aim 1 is designed to establish a causative link between leukemic T cell survival or growth and PKC-theta. We will analyze the expression, intracellular localization and catalytic activity of PKC-theta in several human established T cell leukemia and a murine T cell lymphoma (EL4) in order to determine whether survival or growth of these cells is associated with constitutive PKC-theta activation. We will then determine whether experimental strategies aimed at selectively inhibiting the function of PKC-theta synergize with apoptosis-inducing regimens to facilitate apoptosis of these cells. Conversely, we will determine whether constitutively active PKC-theta confers increased resistance to apoptosis. In Aim 2, we will extend similar analyses to several mouse in vivo models of T cell leukemias in order to determine whether selective PKC-theta-inhibiting pharmacological or genetic strategies inhibit the growth of T cell leukemias in mice, or conversely, whether an active PKC-theta transgene promotes tumor growth. These studies are likely to establish a selective role for PKC-theta in mediating survival signals, which contribute to the growth of T cell leukemias, and validate this T-cell selective enzyme as a therapeutic drug target. Combined with ongoing efforts by several pharmaceutical companies to develop selective PKC-theta inhibitors and available high throughput screening assays, the proposed studies may offer a novel therapeutic strategy for T cell leukemias.