Regulation of Inflammation by Somatostatin via SSTR 2

生长抑素通过 SSTR 2 调节炎症

• 批准号: 6909892
• 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/6909892
• 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）减少小鼠模型和人类疾病的炎症。SOM是在粘膜和炎症部位产生的一种环14氨基酸肽。SOM是由炎性巨噬细胞制造的。SOM可能通过抑制T细胞IFN-？释放。LPS、IFN-?诱导巨噬细胞产生SOM， il - 10, tnf -？PgE2和cAMP。小鼠炎性T细胞仅表达一种SOM受体SSTR2。SSTR2也在患者的炎症部位表达。som介导的IFN-？生产需要功能性SSTR2。该建议的中心假设是，通过SSTIR2受体调节SOM的产生和信号传导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。这项建议有三个具体目标。目的1旨在确定巨噬细胞产生SOM是如何在分子水平上受到调节的。本研究的目的是阐明LPS和IFN-？诱导巨噬细胞SOM表达。Aim 2旨在确定SSTR2如何调节T细胞功能。该目的将确定SSTR2是否与Th1细胞中的磷酸酶和抑制性信号因子偶联以下调IFN-？释放。目的3试图确定去除SOM-SSTR2回路对炎症的体内影响。本目的将利用缺乏SOM或SSTR2的近交小鼠，研究SOM-SSTR2在三种小鼠炎症模型中的免疫调节作用。模型为：TNBS结肠炎、IL - 10缺乏性结肠炎和血吸虫卵肉芽肿。本课题将研究SOM的产生和T细胞介导炎症的调控机制。这些研究将为研究富含内源性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。