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传感器和转录3（STAT3）激活因子的本构活性，这反映了该转录因子在调节凋亡和增殖中的重要性。 STAT3是Th17细胞的TE分化所必需的，Th17细胞是产生促炎性细胞因子IL-17的CD4+辅助T细胞的子集，并且与各种炎症性疾病有关。研究表明，从皮肤T细胞淋巴瘤（CTCL）患者中分离出的T淋巴细胞中的组成型STAT3激活和IL-17产生，这种疾病是恶性T细胞迁移到皮肤的疾病。这些发现表明，由STAT3驱动的TH17细胞分化可能在CTCL和其他T细胞恶性肿瘤的发病机理中起作用。为了检查STAT3在T细胞转化中的作用，开发了一种新型的转基因小鼠模型，其中CD4-CRE诱导了特定于T细胞中的多活跃突变体STAT3（STAT3C）的表达。到六个月大时，CD4-CRE R26STAT3CSTOPFL/+小鼠中有100％发展出一种淋巴增生性疾病，高度让人联想到CTCL。在存在可见的皮肤病理之前，小鼠在淋巴结和皮肤中的Th17细胞水平升高，这表明Th17驱动的低度炎症有助于疾病的发展。 该项目的目的是检查持续的慢性炎症在T细胞的恶性转化中的作用，并发现在细胞转化过程中积累的STAT3信号通路中可逆的表观遗传变化。批准用于临床的有效CTCL疗法是使用组蛋白脱乙酰基酶（HDAC）抑制剂，这表明乙酰化的变化可能有助于CTCL的发病机理，并且发表的观察结果表明HDAC抑制剂可能会调节Stat3的转录活性。所描述的CTCL的STAT3C小鼠模型将用于检查促炎性Th17细胞对CTCL病理学的STAT3驱动分化的贡献，并研究HDAC抑制剂在该疾病中对效应T细胞分化的影响。提出的实验将揭示Th17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T细胞中发生的染色质变化，可能产生新的药物靶标，用于治疗淋巴结恶性肿瘤。 公共卫生相关性：拟议的项目对免疫学和癌症治疗领域具有重要意义，有可能改善淋巴瘤患者的治疗选择和生活质量。这项工作旨在检查慢性炎症在衰弱的疾病发育中的作用，皮肤T细胞淋巴瘤（CTCL）。这项研究将研究炎症性T细胞对CTCL病理学的贡献，并发现免疫细胞信号通路的可逆变化，这些变化可能是新型CTCL疗法和诊断策略的未来靶标。