Regulation of Inflammation by Somatostatin via SSTR 2

生长抑素通过 SSTR 2 调节炎症

• 批准号: 6651104
• 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/6651104
• 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）可减少小鼠模型中的炎症和人类疾病。 SOM 是一种由 14 个氨基酸组成的环状肽，在粘膜和炎症部位产生。 SOM 由炎症巨噬细胞产生。 SOM 可能通过抑制 T 细胞 IFN-α 来调节炎症，发挥关键作用。发布。巨噬细胞 SOM 的产生由 LPS、IFN-α、IL 10、TNF-α、PgE2 和 cAMP 诱导。小鼠炎症 T 细胞仅表达一种 SOM 受体，即 SSTR2。 SSTR2 也在患者的炎症部位表达。 SOM 介导的 IFN-α 抑制生产需要功能性 SSTR2。该提案的中心假设是，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。 SOM 可能是 SOM 丰富的粘膜表面特别重要的免疫调节剂。该提案具有三个具体目标。目标 1 试图确定巨噬细胞 SOM 的产生是如何在分子水平上受到调节的。该目的的目的是阐明 LPS 和 IFN-α 使用的途径。诱导巨噬细胞 SOM 表达。目标 2 旨在确定 SSTR2 如何调节 T 细胞功能。这一目标将确定 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-α？发布。目标 3 试图确定去除 SOM-SSTR2 电路对炎症的体内影响。该目标将使用缺乏 SOM 或 SSTR2 的近交小鼠来研究 SOM-SSTR2 在三种小鼠炎症模型中的免疫调节作用。这些模型包括：TNBS 结肠炎、IL 10 缺陷型结肠炎和血吸虫卵肉芽肿。本提案将研究控制 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。这些研究的结果将为 IBD 和其他炎症性疾病的新疗法提供理论基础。