Regulation of Inflammation by Somatostatin via SSTR 2

生长抑素通过 SSTR 2 调节炎症

• 批准号: 6795585
• 负责人: DAVID E ELLIOTT
• 金额: $ 29.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795585
• 关键词: T lymphocyte; cell line; colitis; enzyme linked immunosorbent assay; flow cytometry; granuloma; histology; hormone receptor; hormone regulation /control mechanism; inflammation; interferon gamma; intestinal mucosa; laboratory mouse; lipopolysaccharides; macrophage; mucosal immunity; neuropeptide receptor; nucleic acid quantitation /detection; protein tyrosine phosphatase; receptor binding; receptor coupling; receptor expression; somatostatin; transfection

DESCRIPTION (provided by applicant): Somatostatin (SOM) decreases inflammation in murine models and human disease. SOM is a cyclic 14 amino acid peptide produced in the mucosa and at sites of inflammation. SOM is made by inflammatory macrophages. SOM may have a critical role regulating inflammation by inhibiting T cell IFN-? release. Macrophage SOM production is induced by LPS, IFN-?, IL 10, TNF-?, PgE2 and cAMP. Murine inflammatory T cells express only one type of SOM receptor, SSTR2. SSTR2 also is expressed at sites of inflammation in patients. SOM-mediated inhibition of IFN-? production requires functional SSTR2. The central hypothesis of this proposal is that the regulation of SOM production and signaling through the SSTIR2 receptor controls Th1 responses in health and disease. SOM may be a particularly important immunomodulator at mucosal surfaces where SOM is plentiful. This proposal has three specific aims. Aim 1 seeks to determine how macrophage production of SOM is regulated at the molecular level. The goal of this aim is to elucidate the pathways used by LPS and IFN-? to induce macrophage SOM expression. Aim 2 seeks to determine how SSTR2 regulates T cell function. This aim will determine if SSTR2 couples to phosphatases and inhibitory signaling factors in Th1 cells to down regulate IFN-? release. Aim 3 seek to determine the in vivo effects of removing SOM-SSTR2 circuitry on inflammation. This aim will use inbred mice that lack SOM or SSTR2 to study the immunoregulatory role of SOM-SSTR2 in three murine models of inflammation. The models are: TNBS colitis, IL 10 deficient colitis, and schistosome egg granulomas.This proposal will study the mechanisms controlling SOM production and regulation of T cell-mediated inflammation. These studies will provide novel insights into the immunoregulation of inflammation at mucosal surfaces rich in endogenous SOM. The results of these studies will provide rationale for novel therapeutic treatment of IBD and other inflammatory diseases.

描述(由申请人提供)：生长抑素(SOM)可减少小鼠模型和人类疾病的炎症。SOM是一种由14个氨基酸组成的环状多肽，产生于粘膜和炎症部位。SOM是由炎性巨噬细胞产生的。SOM可能通过抑制T细胞干扰素？放手。巨噬细胞产生SOM是由内毒素、干扰素-β、IL-10、肿瘤坏死因子-β、前列腺素E_2和环磷酸腺苷诱导的。小鼠炎性T细胞只表达一种类型的SOM受体，SSTR2。SSTR2也在患者的炎症部位表达。SOM介导的干扰素-？生产需要正常运行的SSTR2。这一建议的中心假设是，通过SSTIR2受体调节SOM的产生和信号，控制健康和疾病中的Th1反应。在SOM丰富的粘膜表面，SOM可能是一种特别重要的免疫调节剂。这项提议有三个具体目标。目的1试图确定巨噬细胞如何在分子水平上调节SOM的产生。目的在于阐明内毒素和干扰素的作用途径。诱导巨噬细胞SOM表达。目的2试图确定SSTR2如何调节T细胞功能。这一目标将决定SSTR2是否与Th1细胞中的磷酸酶和抑制信号因子偶联来下调干扰素？放手。目的3探讨去除SOM-SSTR2通路的体内抗炎作用。这一目标将使用缺乏SOM或SSTR2的近交系小鼠来研究SOM-SSTR2在三种炎症模型中的免疫调节作用。这些模型是：TNBS结肠炎、IL-10缺乏性结肠炎和血吸虫卵肉芽肿。这项计划将研究控制SOM产生和调节T细胞介导的炎症的机制。这些研究将为富含内源性SOM的粘膜表面炎症的免疫调节提供新的见解。这些研究结果将为IBD和其他炎症性疾病的新治疗方法提供理论依据。