ABERRANT JAK/STAT SIGNALING IN CUTANEOUS T CELL LYMPHOMA

描述：（改编自申请人摘要）本研究的目的是 明确异常细胞因子信号传导的作用和机制， 在人类皮肤T细胞淋巴瘤（CTCL）的发病机制和进展中的作用。 它将集中在CTCL的Jak/STAT信号通路相关的作用， 与细胞因子受体共用的Y链（YC）一起 由细胞因子刺激，这些细胞因子对于 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途径在CTCL细胞中被激活。而在 不太晚期（低级别/低阶段）的CTCL病例，这种激活似乎 细胞因子诱导，在更晚期（中/高级别/高阶段） 在某些情况下，它是构成性的，至少部分是由于缺乏消极的 通常由SHP-1磷酸酶介导的调节。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以及 该途径的抑制剂（SHP-1磷酸酶和皮亚斯和SOCS蛋白）， 培养和新鲜CTCL细胞。将特别注意 惰性（低）和惰性（低）之间Jak/STAT通路功能的差异 等级/低阶段）和侵略性（中级/高级/高级）类型的 CTCL。在惰性CTCL中，将进行实验以确定 γ c信号细胞因子对于细胞的生长和存活是至关重要的。 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.