STAT3: At the Crossroads of Inflammation and Cancer

STAT3：处于炎症和癌症的十字路口

• 批准号: 8396557
• 负责人: Laura Katherine Fogli
• 金额: $ 3.23万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396557
• 关键词: Acetylation; Aftercare; Age-Months; Alleles; Apoptosis; Asbestos; Asthma; Autoimmunity; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Chromatin; Chronic; Clinic; Cutaneous; DNA Damage; Development; Diagnostic; Disease; Drug Targeting; Epigenetic Process; Exhibits; Future; Genes; Helicobacter pylori; Helper-Inducer T-Lymphocyte; Hepatitis B; Hepatitis C; Histone Deacetylase Inhibitor; Human; Human Papillomavirus; Immune; Immunology; Individual; Inflammation; Inflammatory; Interleukin-17; Knock-in Mouse; Lead; Link; Lung Inflammation; Lymphocyte Activation; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Multiple Myeloma; Mus; Mutate; Mutation; Nature; Nuclear; Pathogenesis; Pathology; Patients; Peptide Hydrolases; Play; Prevention; Production; Psoriasis; Publishing; Quality of life; Receptor Signaling; Regulation; Research; Rheumatoid Arthritis; Role; Sampling; Signal Pathway; Signal Transduction; Skin; Stat3 protein; T cell differentiation; T-Cell Lymphoma; T-Cell Receptor; T-Cell Transformation; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Virus Diseases; Work; cancer therapy; chromatin modification; cigarette smoking; cytokine; improved; interleukin-22; lymph nodes; metaplastic cell transformation; migration; mouse model; mutant; novel; public health relevance; research study; therapeutic target; tissue regeneration; transcription factor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Constitutive activity of signal transducer and activator of transcription 3 (STAT3) is observed in several human cancers, reflecting the importance of this transcription factor in the regulation of apoptosis and proliferation. STAT3 is required for te differentiation of Th17 cells, a subset of CD4+ helper T cells that produces the proinflammatory cytokine IL-17 and has been implicated in various inflammatory disorders. Studies have shown constitutive STAT3 activation and IL-17 production in T lymphocytes isolated from patients with cutaneous T cell lymphoma (CTCL), a disease in which malignant T cells migrate to the skin. These findings indicate that STAT3-driven Th17 cell differentiation may play a role in the pathogenesis of CTCL and other T cell malignancies. To examine the role of STAT3 in T cell transformation, a novel transgenic mouse model was developed in which CD4-Cre induces expression of a hyperactive mutant STAT3 (STAT3C) specifically in T cells. By six months of age, 100% of CD4-Cre R26STAT3Cstopfl/+ mice develop a lymphoproliferative disease highly reminiscent of CTCL. The mice have increased levels of Th17 cells in the lymph nodes and skin before visible skin pathology is present, suggesting that Th17-driven low-grade inflammation contributes to the development of the disease. The aims of this project are to examine the role of sustained chronic inflammation in the malignant transformation of T cells and to uncover reversible epigenetic changes in the STAT3 signaling pathway that accumulate during cellular transformation. An effective CTCL therapy approved for use in the clinic is the use of histone deacetylase (HDAC) inhibitors, suggesting that changes in acetylation may contribute to the pathogenesis of CTCL, and published observations indicate that HDAC inhibitors may modulate the transcriptional activity of STAT3. The described STAT3C mouse model of CTCL will be used to examine the contribution of STAT3-driven differentiation of proinflammatory Th17 cells to CTCL pathology and to investigate the effects of HDAC inhibitors on effector T cell differentiation in the context of this disease. The proposed experiments will reveal the role of a Th17-driven proinflammatory microenvironment in the development of CTCL and other lymphomas and will probe the chromatin changes that occur in T cells during transformation, potentially yielding novel drug targets for the treatment of lymphoid malignancies. PUBLIC HEALTH RELEVANCE: The proposed project has significant implications in the fields of immunology and cancer therapy, potentially improving the treatment options and quality of life for patients with lymphoma. The work is intended to examine the role of chronic inflammation in the development of the debilitating disease, cutaneous T cell lymphoma (CTCL). This research will examine the contribution of inflammatory T cells to CTCL pathology, as well as uncover reversible changes in immune cell signaling pathways that may serve as future targets for novel CTCL therapies and diagnostic strategies.

描述（由申请人提供）：在几种人类癌症中观察到信号转导子和转录激活子3（STAT 3）的组成性活性，反映了该转录因子在细胞凋亡和增殖调节中的重要性。STAT 3是Th 17细胞分化所必需的，Th 17细胞是产生促炎细胞因子IL-17的CD 4+辅助性T细胞的亚群，并且与各种炎性疾病有关。研究表明，从皮肤T细胞淋巴瘤（CTCL）患者分离的T淋巴细胞中存在组成性STAT 3活化和IL-17产生，皮肤T细胞淋巴瘤是一种恶性T细胞迁移至皮肤的疾病。这些发现表明，STAT 3驱动的Th 17细胞分化可能在CTCL和其他T细胞恶性肿瘤的发病机制中发挥作用。为了研究STAT 3在T细胞转化中的作用，开发了一种新的转基因小鼠模型，其中CD 4-Cre特异性地在T细胞中诱导高活性突变体STAT 3（STAT 3C）的表达。到六个月大时，100%的CD 4-Cre R26 STAT 3Cstopfl/+小鼠发展出高度类似CTCL的淋巴组织增生性疾病。在出现可见的皮肤病理之前，小鼠淋巴结和皮肤中的Th 17细胞水平增加，这表明Th 17驱动的低度炎症有助于疾病的发展。 该项目的目的是研究持续的慢性炎症在T细胞恶性转化中的作用，并揭示在细胞转化过程中积累的STAT 3信号通路中的可逆表观遗传变化。批准用于临床的有效CTCL疗法是使用组蛋白脱乙酰酶（HDAC）抑制剂，这表明乙酰化的变化可能有助于CTCL的发病机制，并且已发表的观察结果表明HDAC抑制剂可能调节STAT 3的转录活性。所描述的CTCL的STAT 3C小鼠模型将用于检查促炎性Th 17细胞的STAT 3驱动的分化对CTCL病理的贡献，并研究HDAC抑制剂在这种疾病的背景下对效应T细胞分化的影响。拟议的实验将揭示Th 17驱动的促炎微环境在CTCL和其他淋巴瘤发展中的作用，并将探测T细胞转化过程中发生的染色质变化，可能产生治疗淋巴恶性肿瘤的新药物靶点。 公共卫生关系：该项目在免疫学和癌症治疗领域具有重要意义，可能会改善淋巴瘤患者的治疗选择和生活质量。这项工作旨在研究慢性炎症在皮肤T细胞淋巴瘤（CTCL）发展中的作用。这项研究将研究炎性T细胞对CTCL病理学的贡献，并揭示免疫细胞信号通路的可逆变化，这些变化可能成为新型CTCL治疗和诊断策略的未来目标。