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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要该项目的重点是为年轻人和青少年设计一种新型的受神经支配的微生理系统（MPS）。健康和疾病中的老年脑肠轴 (GBA) GBA 由迷走神经所在的神经回路组成。将肠道内的肠神经系统（ENS）神经元与中枢神经系统（CNS）神经元连接起来，从而允许双向通信需要神经通路的简化模型。从肠道到大脑，健康和疾病的潜在作用机制尚不清楚。迷走神经，主要是位于结状神经节的感觉神经元，传导饮食线索和中枢神经系统肠道细菌发挥作用，并与神经传递性神经退行性疾病有关，例如因此，捕获人类脑肠轴 (GBA) 关键组成部分的 MPS，包括初级中枢后脑神经元、迷走神经元和肠神经元，将是一个有价值的工具了解和操纵年轻和衰老组织的通路功能，并促进发现和这里的方法描述了激光制造、切割和组装的疗法。 MPS 致力于打造人性化的 GBA。我们的多学科团队共同努力 (1) 建立了一个原型。 GBA-MPS，(2) 验证组装的 MPS 内的 3D 神经区室，(3) 展示原始人类神经球来源，以及（4）创建肠道神经结状神经元的转基因模型有两个目标。目标 1 将设计一个 MPS，通过实时电生理学和实时感测 GBA 功能。成像，然后是年轻人和老年人群神经功能的时间过程和终点特征与静态和单一培养进行比较，以确保适当的命运和表型，目标 2 将验证该方法的实用性。该平台通过肠神经元中预先形成的原纤维（PFF）创建疾病模型PD表型年轻和年老的 MPS，并利用表达转基因结节神经元的视蛋白的光刺激，该电路关键，评估神经调节作为减缓帕金森病从肠道扩散到脑室的方法。成功完成第一个模拟人类 GBA 的 MPS 将加速机制研究健康和疾病中的脑肠通讯，并通过分析促进治疗靶标的发现神经生物学和神经退行性疾病的一个可访问且仪器化的 MPS 平台。