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

芯片上的神经血管单元：化学通讯、药物和毒素反应

• 批准号: 8415453
• 负责人: KEVIN D NISWENDER
• 金额: $ 105.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-24 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415453
• 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 Vessels; Blood capillaries; Blood flow; Brain; Brain region; Cell Communication; Cell Culture Techniques; Cells; Cerebrospinal Fluid; Characteristics; Chemicals; Chronic Disease; Clinical; Clinical Trials; Communication; Communities; Coupled; Cytomegalovirus; Development; Devices; Disease; Disease model; Drug toxicity; Elements; Endothelial Cells; Ensure; Feedback; Growth Factor; Hormones; Human; Hypoxia; Immune; Immune system; In Situ; In Vitro; Infection; 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; Phase; Phase I Clinical Trials; Physiological; Physiology; Population; Preparation; Prevention; Process; Property; Research; Research Personnel; Rest; Risk; Role; Screening procedure; 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 metabolism; capillary; cell preparation; cell type; clinical application; clinically relevant; 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; sensor; small molecule; software systems; synergism; theories; trafficking; venule

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. PUBLIC HEALTH RELEVANCE: This research will develop an in vitro microphysiological system representative of a neurovascular unit of the brain that will provide technologies of widespread clinical applicability and reveal new insights into how the brain receives, modifies, and is affected by drugs, other neurotropic agents, and disease. This transformative technological platform, which combines state-of-the art microfluidics, cell culture, analytical instruments, bioinformatics, control theory, and neuroscience drug discovery, will replicate chemical communication, molecular trafficking, and inflammation in the brain. It will enable targeted and clinically relevant nutritional and pharmacologic interventions or prevention of such chronic diseases as obesity and acute injury such as stroke, as well as uncover potential adverse effects of drugs.

描述（由申请人提供）：对全身血流和大脑之间的化学信号进行物理或药理学破坏，影响大脑的正常功能和反应。通过细胞因子、营养物质、生长因子、激素、脂质、神经递质、药物及其代谢物的失调而产生的远程化学信号也很重要，但这些化学信号难以量化，细胞通常是孤立研究的。血脑屏障（BBB）动态地控制着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，也不能用动物模型充分地代表。大多数现有的体外血脑屏障模型不包括含有其他血脑屏障元件的神经元和胶质细胞，不能充分预测药物的疗效和毒性。该研究将开发一种体外、三维、多室、中枢神经系统（CNS）神经血管单元（NVU）和脑脊液（CSF）室的器官型模型，两者都与现实的血液替代供应系统相结合，该系统也包含循环免疫细胞。原代和干细胞衍生的人类细胞将与多种药物相互作用，在血脑屏障和大脑区域之间产生关键的化学通讯，提供一种紧凑的装置，忠实地再现人类血脑屏障、中枢神经系统和脑脊液的特性。提出的体外血脑屏障/中枢神经系统/脑脊液模型体积小，需要有限数量的人类细胞，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。这个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，并将实现有针对性和临床相关的营养和药物干预或预防。该平台将用于检查血脑屏障在调节化学体-脑相互作用中的作用，表征大脑中胶质和神经细胞的相互作用，并评估各种药物，化学品，感染性病原体和异种生物对不同大脑区域的影响。该模型的临床效用取决于它的能力：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的区域；2)使用来自已知病理患者的细胞和液体来评估药物治疗和慢性疾病（如肥胖）和急性损伤（如中风）的生理压力。3)发现药物发现过程中潜在的不良反应以及临床试验中使用的不良反应，例如经批准的药物在脑内皮细胞中的毒性转化；4)发现汇聚在血脑屏障的大量化学信号之间新的和无偏倚的相关性；5)结合微流控装置，最先进的细胞培养和器官型人类脑细胞制剂，分析仪器，生物信息学，控制理论。神经科学药物发现。综合方法将提供广泛适用的技术，并揭示大脑如何接受、修改和受药物、嗜神经药物和疾病影响的新机制和区域特异性见解。