IMMUNOREGULATION BY CORTICOTROPIN RELEASING HORMONE

这项提案的广泛、长期目标是确定如何 神经肽促肾上腺皮质激素释放激素(CRH)调节其活性 在正常和病理条件下的免疫系统。CRH是 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。它还可以在以下位置找到 周围神经和几个器官。免疫调节作用是 从它在体外影响免疫活性细胞的能力来看， 包括其优先刺激肠系膜淋巴结的能力 Peyer‘s斑块B淋巴细胞增殖。其对肠道的作用 相关淋巴组织提示，脑内含有CRH的神经元 胃肠(GI)粘膜参与分泌调节 胃肠道有免疫力。具体目标是1。)CRH的特征 免疫系统中的受体，并决定免疫中的哪些细胞 系统表达CRH受体，2)决定CRH如何影响细胞 在免疫系统中发挥作用，以及3.)确定是正常还是 免疫系统中转化的细胞会产生CRH。实验性的 设计将使用与CRH受体相关的综合方法 CRH对小鼠特定细胞功能的影响 免疫系统。促肾上腺皮质激素释放激素受体的特性和定位 来自大鼠淋巴器官的浓缩淋巴细胞群体将使用 放射性配基结合研究、荧光激活细胞分选仪分析 用荧光CRH类似物和亲和标记。功能性 研究将评估CRH对第二信使系统的影响，以及 促肾上腺皮质激素释放激素对体外B、T淋巴细胞功能测定的影响 包括免疫球蛋白分泌和细胞介导的细胞毒作用。 正常细胞和转化细胞产生CRH的能力将通过 Northern印迹和聚合酶链式反应相结合分析 检测CRH mRNA，放射免疫法检测CRH多肽。更好的 了解CRH在特异性受体介导的调节中的作用 将提供有关外周血细胞的重要信息 神经系统神经肽介导免疫功能和炎症。 这些研究可能在诊断和诊断中具有重要意义 人类疾病的治疗。

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.