ABERRANT JAK/STAT SIGNALING IN CUTANEOUS T CELL LYMPHOMA

描述：(摘自申请者的摘要)本研究的目的是 明确异常细胞因子信号转导的作用和机制 在人皮肤T细胞淋巴瘤(CTCL)的发生和发展中起重要作用。 它将集中在与JAK/STAT相关的信号通路在CTCL中的作用 细胞因子受体共同的Y链(YC)由几个受体共享 受细胞因子的刺激，这些细胞因子对细胞的激活和成熟至关重要 正常T细胞：IL-2、-4、-7、-9和-15。我们的初步数据显示 YC相关的Jak/STAT通路在CTCL细胞中被激活。而在 不太晚期(低级别/低阶段)的CTCL病例出现这种激活 细胞因子诱导，在较晚期(中级/高级/高级阶段) 情况是构成的，至少部分原因是缺乏负面的 调节通常由SHP-1磷酸酶介导。在这项研究中，我们将 详细研究其在恶性细胞中的表达、功能状态和作用 JAK/STAT信号转导通路的转化 这一途径的抑制剂(SHP-1磷酸酶、PIAS和SOCS蛋白) 培养的新鲜CTCL细胞。我们会特别注意 惰性(低)的JAK/STAT通路的功能差异 等级/低阶段)和攻击性(中级/高等级/高阶段)类型 CTCL。在懒惰的CTCL中，将进行实验以确定 YC信号细胞因子对水母细胞的生长和存活至关重要。 恶性T细胞。

DESCRIPTION: (Adapted from applicant's abstract) The purpose of this study is to define the role and understand the mechanisms of aberrant cytokine signaling in the pathogenesis and progression of human cutaneous T-cell lymphoma (CTCL). It will focus on the role in CTCL of the Jak/STAT signaling pathway associated with the cytokine receptor common y chain (yc) shared by several receptor stimulated by cytokines which are critical for activation and maturation of normal T cells: lL-2, -4, -7, -9, and -15. Our preliminary data indicate that the yc-associated Jak/STAT pathway is activated in CTCL cells. Whereas in the less advanced (low grade/low stage) cases of CTCL this activation appears cytokine induced, in the more advanced (intermediate/high grade/high stage) cases it is constitutive and at least in part due to the lack of negative regulation normally mediated by a SHP-1 phosphatase. In this study we will examine in detail the expression, functional status, and role in malignant cell transformation of the Jak/STAT signal transduction pathway as well as inhibitors of this pathway (SHP-1 phosphatase and PIAS and SOCS proteins) using cultured and fresh CTCL cells. Particular attention will be paid to the differences in functioning of the Jak/STAT pathway between the indolent (low grade/low stage) and aggressive (intermediate/high grade/high stage) types of CTCL. In the indolent CTCL, experiments will be performed to determine which of the yc-signaling cytokines is (are) critical for growth and survival of the malignant T cells.