Growth Factors and Inflammatory Bowel Disease

生长因子和炎症性肠病

• 批准号: 8054992
• 负责人: PAULINE K LUND
• 金额: $ 30.95万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054992
• 关键词: Acute; Affect; Alleles; Anchorage-Independent Growth; Animal Model; Apoptosis; Apoptotic; Biochemical; Biological Markers; Boxing; Cancerous; Cell Proliferation; Cell Survival; Cells; Chronic; Colon; Colon Carcinoma; Colonic Neoplasms; Colonoscopy; Colorectal Cancer; Crohn' s disease; Cytokine Inducible SH2-Containing Protein; Cytokine Receptors; Cytokine Signaling; Data; Development; Disease; Dysplasia; Epigenetic Process; Epithelial; Epithelial Cells; Feedback; Follow-Up Studies; Gene Deletion; Gene Expression; Gene Targeting; Genes; Genetic; Growth Factor; Health; Hyperplasia; Immune; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-10; Interleukin-6; Intestines; Knockout Mice; Lesion; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Probes; Mucous Membrane; Mus; Natural regeneration; Neoplasms; Oncogenic; Pathway interactions; Patients; Premalignant; Proteasome Inhibitor; Protein Isoforms; Proteins; Publications; Receptor Signaling; Recovery; Regulation; Risk; Role; STAT3 gene; Signal Transduction; Signaling Pathway Gene; Site; Small Intestinal Neoplasm; Small Intestines; Sodium Dextran Sulfate; Testing; Therapeutic; Transgenes; Tumor Burden; Tumor Necrosis Factor Receptor; Ulcerative Colitis; Work; base; body system; cancer cell; cancer risk; cancer therapy; cell growth; colitis associated cancer; colon cancer cell line; cytokine; design; genetic manipulation; in vivo; inhibitor/antagonist; intestinal epithelium; macrophage; mutant; neoplastic cell; novel; novel strategies; prevent; promoter; recombinase; repaired; research study; response; tumor; tumor progression; tumorigenesis; tumorigenic; villin

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) involve chronic destruction of the intestinal epithelium, and compensatory crypt regeneration and hyperplasia. During IBD, mitogenic and anti-apoptotic effects of cytokines and growth factors help to maintain or restore functional epithelial mass. These same mechanisms, if excessive or prolonged, may promote dysplasia and neoplasia. This proposal will test a central hypothesis that silencing of SOCS3 in intestinal epithelial cells (IEC) promotes inflammation- associated dysplasia and tumorigenesis by limiting the activation of multiple pro-tumorigenic pathways. Preliminary data support a working model that IEC-SOCS3 silencing promotes tumorigenesis by limiting excessive or aberrant activation of STATs, NFkB and TNF receptor 2 (TNFR2). Aim 1 will define the cellular and molecular mechanisms and gene targets associated with enhanced AOM/DSS-induced tumorigenesis in mice with IEC-SOCS3 deletion. Mice with IEC-specific SOCS3 disruption show increased tumor number and size after AOM/DSS. Biochemical, molecular and gene microarray studies will test if loss of SOCS3 enhances activation of STAT and NFkB and their downstream genetic targets, including TNFR2, or novel oncogenic mediators. Aim 2 will define the direct effects of SOCS3 on pro-tumorigenic signaling or transcriptional pathways in IEC or colon cancer cells, and their relevance to tumor cell growth or survival. Non- transformed IEC-6 cells and colon cancer cell lines expressing different levels of endogenous or transgene derived SOCS3, or mutant SOCS3 isoforms, will be used to define mechanisms of action of SOCS3. Constitutive activation or expression of STAT, NFkB or TNFR2, or specific inhibitors of these mediators, will be tested for their ability to reverse the phenotypic or transcriptional effects of SOCS3 over-expression or silencing. Aim #3 will confirm that IEC-SOCS3 deletion promotes dysplasia and tumorigenesis in the IL- 10 null model of IBD and define mechanisms. Mice with combined IEC-specific SOCS3 disruption and IL-10 gene deletion will be used to confirm preliminary data that loss of IEC-SOCS3 promotes spontaneous small bowel tumors and inflammation-associated colon tumors. Biochemical and molecular analyses will test whether similar or distinct signaling pathways and gene targets are affected by SOCS3 in the IL-10 null versus AOM/DSS model Follow up studies will use information from aims 1-3 to design experiments using pharmacological or genetic manipulation of STAT, NF:B or TNFR2 in AOM/DSS or IL-10 null models and define the functional in vivo role of these mediators in transcriptional or tumor-promoting effects of IEC-SOCS3 deletion. PUBLIC HEALTH RELEVANCE: Patients with the inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease have increased colon cancer risk, and chronic inflammation is increasingly linked to cancer. This project tests whether a naturally occurring body protein, suppressor of cytokine signaling 3 (SOCS3), normally reduces or prevents development of colon tumors during intestinal inflammation, and if SOCS3 limits the actions of several molecules known to cause colon cancer. The results will guide and promote use of SOCS3 as a biomarker for cancer risk and assist the development of SOCS3-based therapies as new approaches to prevent colon cancer in IBD.

描述(申请人提供)：炎症性肠病(IBD)涉及肠道上皮的慢性破坏，以及代偿性隐窝再生和增殖。在IBD期间，细胞因子和生长因子的促有丝分裂和抗凋亡作用有助于维持或恢复功能性上皮团块。这些相同的机制，如果过度或延长，可能会促进异型增生和肿瘤的形成。这项提议将检验一个中心假设，即在肠上皮细胞(IEC)中沉默SOCS3通过限制多条促肿瘤途径的激活来促进炎症相关的异型增生和肿瘤的发生。初步数据支持IEC-SOCS3沉默通过限制STATS、NFkB和肿瘤坏死因子受体2(TNFR2)的过度或异常激活来促进肿瘤发生的工作模型。目的1将确定与AOM/DSS诱导的IEC-SOCS3缺失小鼠肿瘤形成增强相关的细胞和分子机制和基因靶点。具有IEC特异性SOCS3干扰的小鼠在AOM/DSS后肿瘤数量和大小增加。生化、分子和基因芯片研究将测试SOCS3的缺失是否会增强STAT和NFkB及其下游遗传靶点，包括TNFR2，或新的致癌介质的激活。目的2将确定SOCS3对IEC或结肠癌细胞中促肿瘤信号或转录途径的直接影响，以及它们与肿瘤细胞生长或存活的相关性。未转化的IEC-6细胞和表达不同水平的内源性或转基因来源的SOCS3或突变的SOCS3亚型的结肠癌细胞株将用于确定SOCS3的作用机制。STAT、NFkB或TNFR2的结构性激活或表达，或这些介质的特定抑制物，将被测试其逆转SOCS3过度表达或沉默的表型或转录效应的能力。目的#3将证实在IL-10缺失的IBD模型中，IEC-SOCS3缺失促进了异型增生和肿瘤的发生，并确定了机制。联合使用IEC特异性SOCS3中断和IL-10基因缺失的小鼠将被用来确认初步数据，即IEC-SOCS3的丢失会促进自发性小肠肿瘤和炎症相关的结肠肿瘤。生物化学和分子分析将测试在IL-10缺失与AOM/DSS模型中SOCS3是否影响相似或不同的信号通路和基因靶点。后续研究将使用AOM/DSS或IL-10缺失模型中STAT、NF：B或TNFR2的药理或遗传操作设计实验，并确定这些介体在IEC-SOCS3缺失的转录或促肿瘤效应中的体内功能作用。公共卫生相关性：炎症性肠病(IBD)、溃疡性结肠炎和克罗恩病患者患结肠癌的风险增加，慢性炎症与癌症的联系日益密切。该项目测试一种自然存在的身体蛋白质，即细胞因子信号转导抑制因子3(SOCS3)，在肠道炎症期间是否正常减少或防止结肠癌的发展，以及SOCS3是否限制已知的几种导致结肠癌的分子的作用。这些结果将指导和促进使用SOCS3作为癌症风险的生物标记物，并帮助开发基于SOCS3的疗法作为预防IBD结肠癌的新方法。