Cholinergic Modulation of Inflammatory CNS Cytokines

除了所提供的空间，我们正在研究神经元-神经胶质相互作用的机制，在促炎症细胞因子和尼古丁胆碱能神经递质系统如何相互作用的背景下，确定神经炎性环境中神经元对兴奋性毒素的敏感性，这在神经疾病中经常存在。总的假设是：中枢神经系统细胞预先暴露于胆碱能激动剂尼古丁，改变了由肿瘤坏死因子启动的信号转导，改变了神经元对兴奋性毒素的易感性和神经炎症过程中的中枢神经系统反应。这一假说源于几个关键的结果，包括：1.培养的大脑皮层神经元可抵抗NMDA毒性的TNFo_2或尼古丁的攻击，然而，当这两种药物同时存在时，TNFc_2和尼古丁诱导的神经保护作用被取消；2.这些药物在强化神经元培养中没有拮抗作用，这表明需要其他非神经元细胞类型；3.在强化神经元培养中加入单核巨噬细胞/小胶质细胞(MP/MG)可以恢复尼古丁和TNFot之间的拮抗作用。4.培养的MP/MG细胞表达nAChRs，它们在功能上对尼古丁的存在有反应；5.尼古丁的加入改变了TnFc启动的caspase8激活的动力学，caspase8是TnFa信号转导的重要的细胞内介质。我们将在特定目标1中确定尼古丁/TNFoc拮抗NMDA的神经保护作用是否需要包括神经元和MP/MG在内的中枢神经系统细胞之间的特异性细胞间相互作用，在特定目标2中，除nAChRo_7外，神经元型尼古丁受体是否参与了与尼古丁/TNFa拮抗神经保护相关的机制(S)，以及在特定目标3中，尼古丁预适应是否通过改变caspase/蛋白水解酶的激活和/或功能来改变其对TNFa的反应。这些研究对于理解尼古丁持续存在对神经炎症的正常调节、确定对多种毒素的易感性以及影响正常和病理表现部位========================================Section End===========================================具有直接和新的意义。

EXCEED THE SPACE PROVIDED, We are examining mechanisms of neuronal-glial interactions within the context of how a pro- inflammatory cytokines and the nicotinic cholinergic neurotransmitter systems interact to determine neuronal susceptibility to excitotoxins in a neuroinflammatory environment, as is often present in neurological disease. The Overall Hypothesis is: Pre-exposure of CNS cells to the cholinergic agonist, nicotine, modifies signaling initiated by TNF_ and alters neuronal vulnerability to excitotoxins and the CNS response during neuro-inflammatory processes. This hypothesis stems from several key results that include: 1. Cultured cortical neurons are protected against an NMDA-toxic challenge by TNFo_ or nicotine, however, TNFc_ and nicotine induced neuroprotection is abolished when the agents are present together cultures of mixed neurons and glia, 2. These agents are not antagonistic in enriched neuronal cultures suggesting that other non-neuronal cell types are required, 3. The addition of mononuclear phagocytes/microglial cells (MP/MG) to enriched neuronal cultures restores antagonism between nicotine and TNFot. 4. MP/MG in culture express nAChRs, and they respond functionally to the presence of nicotine, and 5. Nicotine administration alters the kinetics of TNFc_-initiated caspase 8 activation, an important intracellular mediator of TNFa-signaling. We will determine in Specific Aim 1 if nicotine/TNFoc antagonism of neuroprotection to NMDA requires specific cell-cell interactions between cells of the CNS including neurons and MP/MG, In Specific Aim 2 if neuronal nicotinic receptors, in addition to nAChRo_7, and expressed by cell types other than neurons, participate in mechanism(s) related to nicotine/TNFa antagonism of neuroprotection and in Specific Aim 3 if nicotine preconditioning of CNS cells alters their response to TNFa through modifying caspase/protease activation and/or function. These studies have direct and novel implications toward understanding sustained nicotine presence on the normal regulation of neuro-inflammation determine susceptibility to many toxins and influence normal and pathological PERFORMANCE SITE ========================================Section End===========================================