Neural Simulations as a Tool in Drug Discovery

神经模拟作为药物发现的工具

• 批准号: 7221015
• 负责人: WILLIAM B LEVY
• 金额: $ 24.91万
• 依托单位: INFORMED SIMPLIFICATIONS, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221015
• 关键词: Accounting; Acute Post Traumatic Stress Disorder; Algorithms; Amygdaloid structure; Antidepressive Agents; Behavior; Behavioral; Biochemistry and Pharmacology Cancer Activity; Biological; Biological Process; Biology; Brain; Brain Stem; Brain region; Cell Nucleus; Characteristics; Chromosome Pairing; Cognition; Cognitive; Compatible; Computational algorithm; Computer Simulation; Computer software; Data; Data Set; Development; Disease; Disruption; Dose; Drug Formulations; Drug Receptors; Emotional; Emotions; Experimental Animal Model; Genes; Goals; Hippocampal Formation; Hippocampus (Brain); Housing; Hypothalamic structure; Learning; Mediating; Mental Depression; Modeling; Nature; Neocortex; Neurons; Nightmare; Normal Range; Pathology; Pharmaceutical Preparations; Phase; Post-Traumatic Stress Disorders; Process; Property; Prosencephalon; REM Sleep; Range; Research; Resolution; Selective Serotonin Reuptake Inhibitor; Simulate; Sleep; Specific qualifier value; Speed; Stress; Symptoms; Synapses; System; Technology; Testing; Time; Trauma; United States National Institutes of Health; Validation; addiction; base; computer science; concept; cost; drug development; drug discovery; drug testing; experience; models and simulation; neural model; novel; novel therapeutics; programs; receptor; relating to nervous system; research study; roentgen equivalent man; simulation; theories; tool

DESCRIPTION (provided by applicant): Our long-term goal is to create computational brain simulations sophisticated enough for use in drug testing. This goal is relevant to all houses of NIH seeking pharmacological cures for cognitive, emotional, or behavioral pathologies including addictions and depressions. Drug testing by computer simulations will decrease the cost of drug development and shorten the time required to develop such therapies. It will also help eliminate treatments with undesirable effects on cognition, emotion, and behavior. Using appropriate data sets for studying hippocampal function, we have proof of concept that motivates moving toward this long-term goal. Because neurobiologically-based simulations can predict certain aspects of behavior and cognition, it is time to extend the purview of such simulations to more brain systems and to make such simulations relevant to neuroactive drugs. This application focuses on a particular pathology, severe, acute post-traumatic stress disorder (PTSD). PTSD is distinct from depressions treated by the classic antidepressants and selective serotonin reuptake inhibitors (SSRI's). This application presents a novel, integrated brain theory of PTSD and emphasizes the critical nature of sleep. PTSD not only correlates with poor sleep, but nightmares are the most common symptom in severe, acute PTSD. Experimental animal models already produce data on the effects of trauma on sleep and dreaming; therefore, challenges for the proposed technology are (1) to build a computational model that reproduces such experimental results and (2) to predict novel therapeutic formulations for speeding the improvement of sleep quality, especially dream sleep (REM). The computer simulations will account for interactions at the level of neurons, at the level of synapses, and at the level of drug-receptor interactions. As part of our long-term goal, such software will be able to predict: (1) the effect of gene doses and (2) the effect of behavioral experiences on sleep. Extension of the existing computational models includes additional brain regions and more receptor systems. Moreover, the new software must interface two different styles of brain modeling: one corresponding to the biochemistry and pharmacology of sleep, dreaming, and certain aspects of stress that collapses neurons and synapses into scalar interactions versus the other which corresponds to models and simulations that reproduce contextual and episodic learning by forebrain cortical systems using tens of thousands of neurons and billions of synapses. Specifically, the cognition-mediating system consisting of the hippocampal formation, the basolateral amygdala and neocortex must be interfaced with each other and with the sleep and stress systems, including the n. centralis amygdala (CeA) and several small nuclei located in the brainstem and hypothalamus. Importantly, even if our theory of PTSD is wrong, the software being proposed here has use for modeling competing theories of sleep disruption. Our long-term goal is to create computational brain simulations that are sophisticated enough for drug testing; this goal is relevant to all houses of NIH seeking pharmacological cures for cognitive, emotional, or behavioral pathologies including addictions and depressions. Drug testing by computer simulations will decrease the cost of drug development and shorten the time required to develop such therapies, and it will also help eliminate treatments with undesirable effects on cognition, emotion, and behavior.

描述（由申请人提供）：我们的长期目标是创建计算大脑模拟，足以用于药物测试。该目标与NIH所有房屋有关，以寻求用于认知，情感或行为病理的药理治疗方法，包括成瘾和抑郁症。通过计算机模拟进行药物测试将降低药物开发的成本，并缩短开发此类疗法所需的时间。它还将有助于消除对认知，情感和行为不良影响的治疗方法。使用适当的数据集研究海马功能，我们拥有概念证明，可以促使朝着这个长期目标迈进。由于基于神经生物学的模拟可以预测行为和认知的某些方面，因此是时候将此类模拟的权限扩展到更多的大脑系统，并制作与神经活性药物相关的此类模拟。该应用集中在特定的病理学，严重的急性创伤后应激障碍（PTSD）上。 PTSD与经典抗抑郁药和选择性5-羟色胺再摄取抑制剂（SSRI）治疗的凹陷不同。该应用介绍了一种新颖的，整合的PTSD脑理论，并强调睡眠的批判性质。 PTSD不仅与睡眠不佳有关，而且噩梦是严重的急性PTSD中最常见的症状。实验动物模型已经产生了有关创伤对睡眠和梦想的影响的数据；因此，提议的技术的挑战是（1）建立一个重现此类实验结果的计算模型，以及（2）预测新型的治疗配方，以加快睡眠质量的改善，尤其是Dream Sleep（REM）。计算机模拟将考虑神经元，突触水平以及药物受体相互作用水平的相互作用。作为我们长期目标的一部分，这种软件将能够预测：（1）基因剂量的影响以及（2）行为体验对睡眠的影响。现有计算模型的扩展包括其他大脑区域和更多受体系统。 Moreover, the new software must interface two different styles of brain modeling: one corresponding to the biochemistry and pharmacology of sleep, dreaming, and certain aspects of stress that collapses neurons and synapses into scalar interactions versus the other which corresponds to models and simulations that reproduce contextual and episodic learning by forebrain cortical systems using tens of thousands of neurons and billions of synapses.具体而言，由海马形成，基底外侧杏仁核和新皮层组成的认知中间系统必须彼此连接，并且睡眠和压力系统（包括n）。 Centralis杏仁核（CEA）和位于脑干和下丘脑中的几个小核。重要的是，即使我们的PTSD理论是错误的，这里提出的软件也用于建模竞争性睡眠中断理论。 我们的长期目标是创建足够复杂的药物测试的计算大脑模拟。该目标与NIH所有房屋有关，以寻求用于认知，情感或行为病理的药理治疗方法，包括成瘾和抑郁症。通过计算机模拟进行药物测试将降低药物开发的成本并缩短开发此类疗法所需的时间，并且还将有助于消除对认知，情感和行为不良影响的治疗方法。