Developing a microphysiological system of a humanized Gut-Brain-Axis for age-associated transmissible neuropathologies

开发人性化肠脑轴的微生理系统，用于与年龄相关的传染性神经病理学

• 批准号: 10450941
• 负责人: Abigail Nelson Koppes
• 金额: $ 21.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450941
• 关键词: 3-Dimensional; Affect; Afferent Neurons; Age; Aging; Applications Grants; Autopsy; Biological Models; Biology; Biomedical Engineering; Braak' s hypothesis; Brain; Brain Pathology; Brain Stem; Brain region; Budgets; Calcium; Cell Culture Techniques; Cell physiology; Central Nervous System Diseases; Chemicals; Communication; Complex; Cues; Devices; Disease; Disease Progression; Disease model; Dose; Electrophysiology (science); Engineering; Ensure; Enteral; Enteric Nervous System; Etiology; Evaluation; Free Will; Functional disorder; Grant; Health; Human; Image; In Vitro; Incidence; Individual; Interneurons; Lasers; Methods; Microfabrication; Modeling; Motor; Nerve Degeneration; Nervous System Physiology; Neural Pathways; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropathy; Neurophysiology - biologic function; Neurosphere; Nodose Ganglion; Opsin; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Production; Proteins; Resolution; Resources; Role; Sensory; Series; Source; Specimen; Staging; System; Technology; Testing; Time; Tissues; Transgenic Model; Tweens; Vagus nerve structure; Validation; Work; aged; aging brain; aging population; alpha synuclein; base; design; dietary; disease phenotype; disease transmission; experimental study; genetic manipulation; gut bacteria; gut-brain axis; healthy aging; high reward; high risk; hindbrain; in vivo; in vivo Model; instrument; instrumentation; microphysiology system; multidisciplinary; neural circuit; neural model; neuron component; neuropathology; neuroregulation; neurotransmission; novel; optogenetics; organ on a chip; polydimethylsiloxane; pre-formed fibril; prevent; prototype; relating to nervous system; synaptogenesis; therapeutic target; three dimensional cell culture; tool; trafficking; transmission process

Project Summary This project is focused on engineering a novel innervated microphysiological system (MPS) of the young and aged brain-gut axis (GBA) in health and disease. The GBA is comprised of neural circuits where the vagus nerve connects enteric nervous system (ENS) neurons that reside in the gut to central nervous system (CNS) neurons, thus allowing for bi-directional communication. There is a need for simplified models of the neural pathways from gut-to-brain where the underlying mechanisms of action in health and disease are not well understood. The vagus nerve, predominantly sensory neurons located in the Nodose Ganglia, transduces dietary cues and CNS function by gut bacteria and has been implicated in neurotransmittable neurodegenerative diseases such as Parkinson’s Disease (PD). Thus, an MPS that captures key components of the human brain-gut axis (GBA), including primary central hind brain neurons, vagal neurons, and enteric neurons, would be a valuable tool for understanding and manipulating pathway function in young and aged tissue and for advancing discovery and therapies via neuromodulation. The approach here describes validation of a laser-fabricated, cut & assembled MPS towards a humanized GBA. Our multidisciplinary team has worked together to (1) establish a prototype GBA-MPS, (2) validate 3D neural compartments within assembled MPS, (3) demonstrate primary human neurosphere sourcing, and (4) create a transgenic model of gut innervating nodose neurons. Two aims will be pursued. Aim 1 will engineer an MPS with real-time sensing of GBA function via live electrophysiology and imaging, followed by time-course and end point characterization of neural function in young and aged populations compared to static and monocultures to ensure appropriate fate and phenotype. Aim 2 will validate the utility of the platform to create a disease model PD phenotype by pre formed fibrils (PFFs) in the enteric neurons of the young and aged MPS, and harness photostimulation of opsin expressing transgeneic nodose neurons, the circuit lynchpin, to evalutate neuromodulation as a method to slow PD spread from the gut to the brain compartment. Successful completion of the first ever MPS that simulates human GBA will accelerate the mechanistic study of brain-gut communication in health and disease and advance therapeutic target discovery by enabling analysis of neural biology and neurodegenerative disorders an accessible and instrumented MPS platform.

项目摘要 该项目的重点是工程Young和Young和 健康和疾病的老化大脑轴（GBA）。 GBA由迷走神经的神经回路组成 连接位于肠道中的肠神经系统（ENS）神经元与中枢神经系统（CNS）神经元， 允许双向交流。需要从 肠道脑脑中的健康和疾病中基本作用机制尚不清楚。这 迷走神经，主要是位于鼻神经节中的感觉神经元，可传递饮食线索和中枢神经系统 肠道细菌的功能已在可神经交易的神经退行性疾病中隐含 帕金森氏病（PD）。那是一个捕获人脑肠轴（GBA）的关键组成部分的国会议员， 包括主要的中央后后脑神经元，迷走神经元和输入神经元，将是一个有价值的工具 理解和操纵途径在年轻组织和老年组织中的功能以及进步和进展 通过神经调节疗法。这里的方法描述了激光制作，切割和组装的验证 国会议员朝着人源化的GBA。我们的多学科团队共同努力（1）建立原型 GBA-MP，（2）验证组装MPS内的3D神经室，（3）证明了原代人 神经圈采购，（4）创建了肠道支配淋巴结神经元的转基因模型。两个目标是 追捕。 AIM 1将通过实时电生理学和 成像，其次是年轻人和老年人群中神经功能的时间课程和终点表征 与静态和单一培养物相比，以确保适当的命运和表型。 AIM 2将验证效用 通过预先形成的原纤维（PFF）在Enter的Enter神经元中创建疾病模型PD表型的平台 年轻的和老化的MPS，以及表达经循环淋巴结神经元的Opsin的光静态刺激，电路 lynchpin，评估神经调节作为一种减慢PD从肠道传播到脑部室的方法。 成功完成模拟人类GBA的第一个国会议员将加速 健康和疾病中的脑脉络沟通以及通过启用分析来提高热目标发现 神经生物学和神经退行性疾病是一种可访问的仪器MPS平台。