The Role of IL-1beta in Neurosecretory Function

描述（由申请人提供）：我们的工作假设是， 白细胞介素-1-β在介导细胞间 在中枢神经系统的沟通。有趣的是， IL-1-β的活性通常决定其活性是有益还是有害 to brain脑function功能.神经胶质源性IL-1-β主要与 病理生理状况，包括炎症和神经退行性疾病 紊乱相比之下，神经元IL-1-β似乎在细胞凋亡中起关键作用。 调节特定的脑功能， 在正常生理条件下的旁分泌信号分子。然而，在这方面， 关于其作用机制知之甚少， 这个实验室和其他实验室已经证明，IL-1-β存在于 大细胞催产素（OT）和加压素（VP）神经元 神经分泌系统（MNS），其中它可以调节OT的神经分泌 和VP通过影响神经元-胶质细胞的相互作用。我们的长期目标是 利用MNS作为模型系统，阐明 神经元IL-1-β调节神经元-神经胶质相互作用和神经分泌 CNS中的活动。拟议研究的具体目标是：1） 研究神经元IL-1-β和 IL-1-β受体1型基因表达可能改变; 2）证实并延长 我们的初步观察提供了有力的证据， 神经元IL-1-β从神经分泌末梢的活性依赖性释放。 我们的目标将通过量化 放射自显影原位杂交分析和定量酶联 在钾诱发的IL-1-β释放后，通过免疫测定法（ELISA）从 单个神经叶（NL）外植体保持在培养物中。R 03机制 将允许PI建立原位杂交组织化学， 放射自显影和ELISA技术对于追求这些和未来至关重要 目标.实现这些具体目标将增加我们对以下方面的了解： 细胞因子影响神经元-胶质细胞相互作用的机制， 中枢神经系统的神经分泌活动，这些见解反过来可能表明， 神经免疫、神经内分泌和神经系统疾病中细胞因子治疗的创新方法 整个神经系统的神经退行性疾病。

DESCRIPTION (provided by applicant): Our working hypothesis is that interleukin-1-beta plays a fundamental role in mediating intercellular communication in the central nervous system. Interestingly, the cellular source of IL-1-beta often determines whether its activity is beneficial or deleterious to brain function. Glial-derived IL-1-beta is predominantly associated with pathophysiological conditions, including inflammatory and neurodegenerative disorders. In contrast, neuronal IL-1-beta appears to play a critical role in modulating specific brain functions by acting as either an autocrine or paracrine signaling molecule under normal physiological conditions. However, little is known regarding the mechanisms of its actions Recent findings from this and other laboratories have demonstrated that IL-1-beta is present in the oxytocin (OT) and vasopressin (VP) neurons of the rat magnocellular neurosecretory system (MNS) where it may act to modulate neurosecretion of OT and VP by influencing neuronal-glial interactions. Our long-term objectives are to utilize the MNS as a model system for elucidating the mechanisms by which neuronal IL-1-beta modulates neuronal-glial interactions and neurosecretory activity in the CNS. The specific objectives of the proposed studies are to: 1) investigate the physiological conditions under which neuronal IL-1-beta and IL-1-beta receptor type 1 gene expression may be altered; 2) confirm and extend our preliminary observations which provided strong evidence for activity-dependent release of neuronal IL-1-beta from neurosecretory terminals. Pursuit of our objectives will be accomplished using quantitative autoradiographic in situ hybridization analysis and quantitative enzyme-linked immunoassay (ELISA) following potassium-evoked release of IL-1-beta from individual neural lobe (NL) explants maintained in culture. The R03 mechanism will allow the PI to establish the in situ hybridization histochemistry, autoradiographic and ELISA techniques critical for pursuit of these and future objectives. Fulfillment of these specific aims will increase our knowledge of the mechanisms by which cytokines affect neuronal-glial interactions and neurosecretory activity in the CNS, insights that could in turn suggest innovative approaches for cytokine therapies in neuroimmune, neuroendocrine and neurodegenerative disorders throughout the nervous system.