Simulation-guided Nicotinic Synapse & Alzheimer's Disease Drug Mechanisms

描述（由申请人提供）：胆碱能系统向大脑的几乎每个区域提供弥漫神经支配，并驱动或调节各种各样的行为。尼古丁乙酰胆碱受体（nachr）与许多疾病有关，如癫痫、成瘾、精神分裂症、帕金森病、血管性痴呆、路易体痴呆和阿尔茨海默病。在这个应用中，我们提出了与突触功能的计算机模型交互耦合的实验。计算机模型旨在成为增强实验者对基本突触机制、药理学和疾病的见解的通用工具。我们通过关注烟碱突触的拟胆碱药物来启动这种方法。这类药物是目前唯一被批准用于治疗轻度至中度阿尔茨海默病（AD）的药物。工作假设是，胆碱能药物在烟碱性胆碱能突触中具有不同的机制作用，并且通过影响nachr，这些药物也影响其他神经递质的释放。我们的目标是通过三个层次的交互建模和实验来实现这种方法。在每个层面上，我们都使用文献中的数据来开发初步的计算机模型。这些模型产生的模拟可以指导实验的设计和解释。在模拟和实验交互的第一层次，我们在组织培养和切片中应用膜片钳电生理学来确定nachr的激活和脱敏参数。这些基本数据补充了文献中的数据，使我们能够开发出将在整个研究中使用的可靠的nAChR动力学模型。在相互作用的第二级，我们使用电生理学来检查烟碱突触的拟胆碱药物的药理学。实验由中枢神经系统尼古丁突触模型指导和解释。在第三个层面，我们使用循环伏安法在纹状体脑切片中检查胆碱能/多巴胺能相互作用，由相互作用的中枢神经系统突触模型指导。这里提出的工作将作为未来扩展神经递质系统之间的网络相互作用和未来应用于其他神经系统疾病的基础。

DESCRIPTION (provided by applicant): Cholinergic systems provide diffuse innervation to nearly every area of the brain, and drive or modulate a wide variety of behaviors. Nicotinic acetylcholine receptors (nAChRs) have been implicated in many diseases, such as epilepsy, addiction, schizophrenia, Parkinson's disease, vascular dementia, dementia with Lewy bodies, and Alzheimer's disease. In this application, we propose experiments that are interactively coupled to computer models of synaptic function. The computer models are intended to be generalized tools that enhance the experimentalist's insights into basic synaptic mechanisms, pharmacology, and disease. We are initiating this approach by focusing on cholinomimetic drugs at nicotinic synapses. Such drugs are now the only approved treatments for mild to moderate Alzheimer's disease (AD). The working hypothesis is that the cholinergic drugs have varied mechanistic effects at nicotinic cholinergic synapses, and by affecting nAChRs, these drugs also influence the release of other neurotransmitters. Our aim is to implement this approach with three levels of interactive modeling and experimentation. At each level we have used data from the literature to develop preliminary computer models. The models produce simulations that guide the design and interpretation of the experiments. At the first level of interaction between simulations and experimentation, we apply patch-clamp electrophysiology in tissue culture and slice to determine activation and desensitization parameters for the nAChRs. These basic data supplement those from the literature, enabling us to develop reliable models of nAChR kinetics that will be used throughout this research. At the second level of interaction, we use electrophysiology to examine the pharmacology of cholinomimetic drugs at nicotinic synapses. The experiments are guided and the interpretation assisted by a model of a CNS nicotinic synapse. At the third level, we use cyclic voltammetry in striatal brain slices to examine cholinergic/dopaminergic interactions guided by a model of interacting CNS synapses. The work proposed here will serve as the basis for future extensions to network interactions among neurotransmitter systems and future applications to other neurological diseases.