Neurovascular Unit on a Chip: Regional Chemical Communication, Drug and Toxin Responses

芯片上的神经血管单元：区域化学通讯、药物和毒素反应

基本信息

批准号：
9265564
负责人：
Chaitali Ghosh
金额：
$ 15.6万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-24 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265564
关键词：
Acute Address Adverse drug effect Adverse effects Affect Animal Model Arts Astrocytes Bioinformatics Biological Biological Assay Biology Blood Blood - brain barrier anatomy Blood capillaries Brain Brain region Cell Communication Cell Culture Techniques Cells Cerebrospinal Fluid Cerebrovascular Circulation Characteristics Chemicals Chronic Disease Clinical Clinical Trials Communication Communities Coupled Cytomegalovirus Infections Development Devices Disease Disease model Drug toxicity Elements Endothelial Cells Ensure Feedback Growth Factor Gene Health Hormones Human Hypoxia Immune Immune system In Situ In Vitro Infectious Agent Inflammation Injury Intervention Ischemia Leukocytes Lipids Liquid substance Mass Spectrum Analysis Metabolic Metabolism Microfluidic Microchips Microfluidics Modeling Molecular Morbidity - disease rate Neuraxis Neuroglia Neurons Neurosciences Neurotransmitters Nutrient Nutritional Obesity Pathology Patients Pericytes Pharmaceutical Preparations Pharmacotherapy Phase Phase I Clinical Trials Physiological Physiology Population Preparation Prevention Process Property Research Research Personnel Rest Risk Role Series Signal Transduction Stem cells Stress Stroke Structure of choroid plexus Synapses System Techniques Technology Testing Time Toxin Validation Xenobiotics body system brain cell brain endothelial cell brain metabolism capillary cell preparation cell type clinical application clinically relevant control theory cytokine design drug discovery drug efficacy experience in vitro Model insight instrument instrumentation ion mobility mass spectrometer mind body interaction mortality neuropharmacologic agent neurotoxicity neurotropic neurovascular unit novel programs relating to nervous system response screening sensor small molecule software systems synergism trafficking venule

项目摘要

DESCRIPTION (provided by applicant): Physical or pharmacological disruption of chemical signals between the systemic blood flow and the brain im- pairs normal functioning and responsiveness of the brain. Long-range chemical signaling through dysregulation of cytokines, nutrients, growth factors, hormones, lipids, neurotransmitters, drugs and their metabolites is also important, but these chemical signals are difficult to quantify and cells are usually studied n isolation. The blood-brain barrier (BBB) dynamically controls exchange between the brain and body, but this cannot be studied directly in the intact human brain or adequately represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and cannot adequately predict drug efficacy and toxicity. This research will develop an in vitro, three-dimensional, multi-compartment, organotypic model of a central nervous system (CNS) neurovascular unit (NVU) and cerebral spinal fluid (CSF) compartment, both coupled to a realistic blood-surrogate supply system that also incorporates circulating immune cells. Primary and stem-cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions, providing a compact device that faithfully reproduces the properties of the human BBB, the CNS, and the CSF. The proposed in vitro BBB/CNS/CSF model will have a small volume, requires a limited number of human cells, can recreate interactions between different brain regions, and will be coupled in real time to advanced electrochemical and mass spectrometry instruments. This transformative technological platform will replicate chemical communication, molecular trafficking, and inflammation in the brain, and will enable targeted and clinically relevant nutritional and pharmacologic interventions or prevention. This platform will be used to examine the role of the BBB in modulating chemical body-brain interactions, characterize glial and neural cell interactions in the brain, and assess the effect of a wide range of drugs, chemicals, infectious agents and xenobiotics on various brain regions. The model's clinical utility rests on its ability to 1) recreate unique regions by selecting specific combinations of neurons, endothelial cells, astrocytes, other neuroglia, pericytes and systemic leukocytes, 2) use cells and fluids derived from patients with known pathologies to assess drug treatments and physiological stress from chronic diseases such as obesity and acute injury such as stroke, 3) uncover potential adverse effects during drug discovery as well as those that are being used in clinical trials, such as toxic transformation of approved drugs by brain endothelial cells, 4) detet novel and unbiased correlations between large numbers of chemical signals which converge at the BBB, and 5) combine microfluidic devices, state-of-the-art cell culture and organotypic human brain-cell preparations, analytical instruments, bioinformatics, control theory, and neuroscience drug discovery. An integrated approach will provide technologies of widespread applicability and reveal new mechanistic and region-specific insights into how the brain receives, modifies, and is affected by drugs, neurotropic agents and disease.

描述（由申请人提供）：全身血流和大脑之间化学信号的物理或药理学破坏会损害大脑的正常功能和反应能力。通过细胞因子、营养物质、生长因子、激素、脂质、神经递质、药物及其代谢物失调产生的长程化学信号也很重要，但这些化学信号很难量化，通常是在分离的情况下研究细胞。血脑屏障（BBB）动态控制大脑和身体之间的交换，但这不能直接在完整的人脑中进行研究，也不能通过动物模型充分代表。大多数现有的体外 BBB 模型不包括具有其他 BBB 元件的神经元和神经胶质细胞，无法充分预测药物疗效和毒性。这项研究将开发一个中枢神经系统 (CNS) 神经血管单元 (NVU) 和脑脊髓液 (CSF) 室的体外、三维、多室器官模型，两者均与真实的血液替代供应系统耦合它还包含循环免疫细胞。原代细胞和干细胞衍生的人类细胞将与多种试剂相互作用，在血脑屏障和大脑区域之间产生关键的化学通讯，从而提供一个紧凑的装置，忠实地再现人类血脑屏障、中枢神经系统和脑脊液的特性。拟议的体外 BBB/CNS/CSF 模型体积较小，需要有限数量的人体细胞，可以重建不同大脑区域之间的相互作用，并将实时耦合到先进的电化学和质谱仪器。这一变革性的技术平台将复制大脑中的化学通讯、分子运输和炎症，并将实现有针对性的、临床相关的营养和药理学干预或预防。该平台将用于检查 BBB 在调节化学体脑相互作用中的作用，表征大脑中的神经胶质细胞和神经细胞相互作用，并评估各种药物、化学品、感染剂和异生物质对各种大脑的影响地区。该模型的临床实用性取决于其以下能力：1) 通过选择神经元、内皮细胞、星形胶质细胞、其他神经胶质细胞、周细胞和全身白细胞的特定组合来重建独特区域，2) 使用来自已知病理患者的细胞和液体来评估药物治疗以及肥胖等慢性疾病和中风等急性损伤带来的生理压力，3) 发现药物发现过程中以及临床试验中使用的潜在副作用，例如已批准药物的毒性转化脑内皮细胞，4) 检测聚集在 BBB 的大量化学信号之间新颖且公正的相关性，5) 结合微流体装置、最先进的细胞培养和器官型人脑细胞制剂、分析仪器，生物信息学、控制理论和神经科学药物发现。综合方法将提供广泛适用的技术，并揭示大脑如何接收、修改以及受药物、神经营养剂和疾病影响的新机制和特定区域的见解。