Mechanisms of TNFa Enhancement of Nicotinic Receptor Upregulation

TNFa增强烟碱受体上调的机制

基本信息

批准号：
8507186
负责人：
LORISE C GAHRING
金额：
$ 34.46万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-18 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507186
关键词：
Address Affinity Aging Agonist Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Asthma Attention Back Behavior Binding Sites Blood Vessels Brain Brain Pathology Cell Communication Cell Culture Techniques Cell physiology Cells Chronic Obstructive Airway Disease Coculture Techniques Cyclic AMP-Dependent Protein Kinases Cytokine Signaling Disease Dissection Endocrine system Endothelial Cells Equilibrium Etiology Genetic Variation Goals Immune Immune system Individual Inflammation Inflammatory Inflammatory Bowel Diseases Insulin Resistance Interleukins Lead Ligand Binding Ligands Link Malignant Neoplasms Measurement Measures Mediating Metabolic Microglia Modeling Mus Neuraxis Neuroglia Neurons Nicotine Nicotine Dependence Nicotinic Receptors Organ Outcome Parkinson Disease Pathway interactions Peripheral Phase Phosphorylation Phosphorylation Site Physiological Physiological Processes Predisposition Primary Cell Cultures Process Property Relative (related person)Reporting Resolution Role Signal Pathway Signal Transduction Signal Transduction Pathway Skin Specificity System Therapeutic Agents Therapeutic Intervention Tissues Tumor Necrosis Factor-alpha Up-Regulation addiction animal tissue autocrine cytokine density feeding genetic manipulation interest macrophage mouse model neuroprotection nicotine abuse paracrine premature receptor receptor expression receptor upregulation research study response trafficking

项目摘要

ABSTRACT Nicotine imparts its effects on cellular function through interaction with neuronal nicotinic acetylcholine receptors (nAChR). Some of these receptors, especially those composed of a4b2 subunits, respond to sustained ligand exposure through the process of upregulation as defined by a substantial increase in the density of high affinity nicotine binding sites. The physiological consequences of upregulation have been linked to many diverse processes ranging from addiction to pathophysiological processes contributing to early phases of Alzheimers disease. An exciting and relatively new role for nAChRs is emerging with regard to the interaction with pro-inflammatory cytokines. In fact, the anti-inflammatory properties of nicotine, acting through various nAChRs, is now widely reported to influence many diseases of inflammatory etiology. However, relatively little is known about the mechanisms controlling the inflammatory:nAChR interaction. The overall goal of this proposal is to define intracellular mechanisms that regulate the interactions between key pro- inflammatory cytokines and defined combinations of nAChR subtypes. SPECIFIC AIM 1. Hypothesis: TNFa-activation of the p38MAPK pathway and/or IL-1b activation of PKA pathways enhance a4b2 expression and these are antagonized by pathways involving PI3K/Akt signaling. In this Aim we will pursue the definition of intracellular pathways initiated by TNFa and/or IL-1b to enhance nicotine-mediated upregulation of nAChRa4b2. SPECIFIC AIM 2. Hypothesis: Direct phosphorylation of a4 and the presence of other nAChR subunits modify the pro-inflammatory cytokine signals mediating enhanced upregulation of a4b2. This Aim will determine the impact of: 1) modifying PKA phosphorylation sites in a4; 2) introducing (or deleting) other nAChRs (specifically a7 or a5); and 3) determining effects of TNFa or IL-1b intracellular signaling leading to enhanced a4b2 upregulation in cultured neurons. SPECIFIC AIM 3. Hypothesis: Interactions between cells of the CNS such as neurons and microglia (Mg) direct the outcome of the overall inflammatory:nAChR response. Neurons and microglia will be co-cultured in different ratios to dissect the relative contribution of paracrine, autocrine or juxtacrine interactions in modulating the TNFa and IL-1b-mediated enhancement of a4b2-upregulation in a mixed cell system.

抽象的尼古丁通过与神经元烟碱乙酰胆碱的相互作用来赋予其对细胞功能的影响受体（NACHR）。其中一些受体，尤其是由A4B2亚基组成的受体，对持续通过上调过程的配体暴露，这是由高密度大大增加所定义的亲和尼古丁结合位点。上调的生理后果与许多从成瘾到病理生理过程的各种过程，导致了早期阶段阿尔茨海默氏病。 NACHRS的一个令人兴奋且相对较新的角色正在出现在互动方面促炎细胞因子。实际上，尼古丁的抗炎特性，通过各种 NACHRS现在被广泛报道会影响许多炎症病因的疾病。但是，相对关于控制炎症的机制知之甚少：NACHR相互作用。总体目标该建议是定义细胞内机制，这些机制调节了关键方案之间的相互作用 NACHR亚型的炎性细胞因子和定义的组合。特定目标1。假设：p38mapk途径和/或IL-1B激活PKA的TNFA激活途径增强了A4B2的表达，这些表达与涉及PI3K/AKT信号传导的途径相拮抗。在我们将追求TNFA和/或IL-1B发起的细胞内途径的定义以增强尼古丁介导的NACHRA4B2上调。特定目的2。假设：A4的直接磷酸化和其他NACHR亚基的存在修改促炎性细胞因子信号介导A4b2的上调。这个目标确定：1）在A4中修改PKA磷酸化位点； 2）引入（或删除）其他 NACHRS（特别是A7或A5）； 3）确定TNFA或IL-1B细胞内信号传导的影响在培养的神经元中增强了A4B2上调。特定目的3。假设：CNS细胞（例如神经元和小胶质细胞（MG））之间的相互作用指导整体炎症的结果：NACHR反应。神经元和小胶质细胞将共同培养不同的比率是剖析旁分泌，自分泌或近距离相互作用的相对贡献调节混合细胞系统中A4B2上调的TNFA和IL-1B介导的增强。