Molecular Pathways of Interleukin-13 in Cutaneous T-cell Lymphoma

摘要 皮肤T细胞淋巴瘤（CTCL）是一组异质性的T淋巴细胞 主要影响皮肤的恶性肿瘤。蕈样肉芽肿（MF）是最常见的 CTCL的形式，并且通常进行惰性课程。然而，在相当数量的 病人的疾病可能会进展和肿瘤细胞扩散到身体的其他部位 导致致命的后果。MF的诊断，特别是在早期阶段，很难， 由于缺乏恶性淋巴细胞的特异性标志物，有限 晚期MF患者有治疗选择，这反映了 对疾病的发病机理认识不足。 我们最近证明IL-13及其受体代表了一种新的肿瘤标志物， 恶性MF。我们的研究进一步表明IL-13信号通过信号转导途径。 转导和转录激活因子-6（STAT-6）蛋白。值得注意的是，我们发现 MF患者受影响皮肤中大量活化STAT-6+细胞， 处于晚期在这里，我们建议分析IL-13的分子途径， 恶性细胞中来自侵袭性MF的信号传导。我们的核心假设是 STAT-6是MF发病机制中的一个主要因素，其在促进MF发病中起关键作用。 疾病进展并代表治疗的潜在靶点。具体 本提案的目的是牢固地建立在我们以前的成果基础上，并侧重于确定 STAT-6在MF发病机制中的独特作用，从而阐明了 MF中IL-13诱导肿瘤细胞增殖的分子机制 确定MF发病机制将揭示新的诊断剂， 分子靶点，导致针对这种疾病的创新疗法。

Abstract Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T lymphocytes malignancies that primarily affect skin. Mycosis fungoides (MF) is the most common form of CTCL and typically runs an indolent course. However, in a significant number of patients the disease may progress and tumor cells spread to other sites of the body leading to a fatal outcome. Diagnosis of MF, especially in the early stages, is difficult to establish due to the absence of specific markers for malignant lymphocytes. Limited treatment options are available for patients with advanced-stage MF, a reflection of the poor understanding of disease pathogenesis. We have recently demonstrated that IL-13 and its receptors represent novel markers of malignancy in MF. Our studies further implicated IL-13 signaling via the Signal Transducer and Activator of Transcription-6 (STAT-6) protein. Significantly, we found high numbers of activated STAT-6+ cells in the affected skin of MF patients, particularly in advanced stages. Here we propose to analyze the molecular pathways of IL-13 signaling in malignant cells from aggressive forms of MF. Our central hypothesis is that STAT-6 is a major factor in the pathogenesis of MF that is critical in promoting disease progression and represents a potential target for therapy. The Specific Aims of this proposal are based solidly on our previous results and focus on identifying the unique role of STAT-6 in the pathogenesis of MF, thus shedding light on the molecular mechanisms underlying IL-13-induced tumor cell proliferation in MF. Identifying the mechanisms of MF pathogenesis will reveal novel diagnostic agents and molecular targets, leading to innovative therapies against this disease.