IMMUNOREGULATION BY CORTICOTROPIN-RELEASING HORMONE

这项建议的广泛和长期目标是确定 神经肽促肾上腺皮质激素释放激素（CRH）调节活性 免疫系统在正常和病理条件下的变化。 华润集团为 神经内分泌的主要中枢神经系统调节器， 自主神经和对压力的行为反应 也存在于 周围神经和几个器官。 免疫调节作用是 通过其在体外影响免疫活性细胞的能力表明， 包括其优先刺激肠系膜淋巴结的能力 和派伊尔集合淋巴结B淋巴细胞增殖。 其对肠道的活性 相关淋巴组织表明，CRH含有神经元， 胃肠道（GI）粘膜参与调节分泌 胃肠道的免疫力 具体目标是1）。表征CRH 免疫系统中的受体，并决定免疫系统中的哪些细胞 系统表达CRH受体，2）确定CRH如何影响细胞 在免疫系统中发挥作用，以及3.）确定是否正常或 免疫系统中的转化细胞产生CRH。 实验 设计将使用与CRH受体相关的综合方法 CRH对特定细胞功能的影响， 免疫系统 CRH受体的表征和定位 来自大鼠淋巴器官的富集淋巴细胞群将使用 放射性配体结合研究，荧光激活细胞分选仪分析 用荧光素化的CRH类似物和亲和标记。 功能 研究将评估CRH对第二信使系统的影响， CRH对体外测定的B和T淋巴细胞功能的影响， 包括免疫球蛋白分泌和细胞介导的细胞毒性。 正常和转化细胞的CRH产生将通过 结合北方印迹和聚合酶链反应分析， 检测CRH mRNA，放射免疫法检测CRH肽。 更好的 了解CRH在特异性受体介导的调节中的作用 将提供重要的信息， 神经系统神经肽介导免疫功能和炎症。 这些研究可能对诊断有重要意义， 治疗人类疾病。

The broad, long-term objective of this proposal is to determine how the neuropeptide corticotropin releasing hormone (CRH) modulates the activity of the immune system under both normal and pathologic conditions. CRH is the major central nervous system regulator of the neuroendocrine, autonomic, and behavioral responses to stress. It is also found in peripheral nerves and in several organs. An immunoregulatory role is suggested by its ability to influence immunocompetent cells in vitro, including its ability to preferentially stimulate mesenteric lymph node and Peyer's patch B-lymphocyte proliferation. Its activity on gut associated lymphoid tissue suggests that CRH containing neurons in gastrointestinal (GI) mucosa are involved in modulation of secretory immunity in the GI tract. The specific aims are to 1.) characterize CRH receptors in the immune system and determine which cells in the immune system express CRH receptors, 2) determine how CRH effects cellular function in the immune system, and 3.) determine whether normal or transformed cells in the immune system produce CRH. The experimental design will use an integrated approach which correlates CRH receptor characterization with the effect of CRH on specific cell functions in the immune system. CRH receptor characterization and localization on enriched populations of lymphocytes from rat lymphoid organs will use radioligand binding studies, fluorescence activated cell sorter analysis with fluoresceinated CRH analogs, and affinity labelling. Functional studies will assess the effect of CRH on second messenger systems, and on the effect of CRH on in vitro measures of B and T lymphocyte function, including immunoglobulin secretion and cell mediated cytotoxicity. Production of CRH by normal and transformed cells will be assessed by a combination of northern blot and polymerase chain reaction analysis to detect CRH mRNA, and radioimmunoassay to detect CRH peptides. A better understanding of the role of CRH in specific receptor mediated modulation of immune function will provide important information on how peripheral nervous system neuropeptides mediate immune function and inflammation. These studies could have important implications in the diagnosis and treatment of human disease.