Microphysiological System for the Human Hippocampal Dentate Gyrus-CA3 Circuit

人类海马齿状回-CA3 回路的微生理系统

• 批准号: 10057728
• 负责人: David W Nauen
• 金额: $ 23.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057728
• 关键词: Address; Anatomy; Architecture; Biological; Biological Models; Brain; Brain Pathology; Brain region; Cell Culture Techniques; Cell Separation; Cell physiology; Cells; Characteristics; Charge; Communities; Dementia; Deposition; Development; Disease; Epilepsy; Extracellular Matrix; Family; Functional disorder; Growth; Health; Hippocampus (Brain); Human; Hyaluronic Acid; In Vitro; Individual; Investigation; Liquid substance; Location; Mechanics; Membrane; Memory; Mental Depression; Methods; Microfluidics; Modeling; Modification; Nervous system structure; Neuroglia; Neurons; Neurosciences; Nutrient; Optics; Organoids; Parahippocampal Gyrus; Pathology; Pattern; Positioning Attribute; Process; Property; Public Health; Recreation; Reproducibility; Signaling Molecule; Signaling Protein; Specific qualifier value; Structure; Study models; Surface; System; Techniques; Technology; Temporal Lobe Epilepsy; Testing; Tissues; To specify; Trauma; base; brain cell; cell growth; cell type; dentate gyrus; design; extracellular; facsimile; falls; improved; in vivo; induced pluripotent stem cell; innovation; insight; microphysiology system; model development; nervous system disorder; neural circuit; neural model; novel; precursor cell; progenitor; scaffold; stem cell technology; stem cells; tool; voltage

Project Summary To reduce the burden of neurological disease, induced pluripotent stem cell-derived human brain cells offer the potential for unprecedented insight. But the capabilities of the nervous system arise from the interactions of its cells, so to use them as a model of brain pathology, they must be investigated in a context where they can reciprocally influence one another as they do in vivo. The field is in need of facsimiles with architectural arrangements that recapitulate brain circuits. To study the dentate gyrus-hippocampal CA3 circuit that is critical for memory and often altered in diseases such as epilepsy, this project will place neuronal and glial precursor cells at precise locations. The project consists of two aims. First, we will create a matrix suitable for capture of fluid droplets containing individual glial and neuronal cells. This surface must be soft enough to minimize cell trauma during deposition and must encourage the growth of these cells and extension of their processes. A porous scaffold constructed of the brain extracellular component hyaluronic acid is the starting point for development of this capture substrate. Embedding of signaling molecules will help specify cell identities and encourage cell growth, and regional modulation of matrix properties will help guide cell organization. Secondly, adapting methods from cell-sorting technology, we will develop a microfluidic system for optical cell identification. When the droplet containing the cell is released, a charge is applied. As the droplet falls through a voltage field, this charge determines its position. In this way cells will be deposited in precise patterns. The resulting array of neurons and glial cells will yield a robust, reproducible model -- composed of human brain cells -- of neural circuit function and pathology. Given the great toll of neurologic diseases involving hippocampus such as epilepsy, depression, and dementia, improved means of investigating these conditions and possible treatments could benefit millions of individuals and families. Indeed, this project will provide a framework for construction of a microphysiological system to model any brain circuit. This has potential to yield significant value to public health.

项目摘要 为了减轻神经疾病的负担，诱导多能干细胞衍生的人脑细胞提供 前所未有的见识的潜力。但是神经系统的功能来自互动 它的细胞，以便将它们用作脑病理学的模型，必须在它们的情况下进行研究 可以像体内一样相互影响。该领域需要带有建筑的传真 概括脑电路的安排。 研究对记忆至关重要的齿状回齿轮 - 海马CA3电路 例如癫痫病，该项目将在精确的位置放置神经元和神经胶质前体细胞。项目 由两个目标组成。首先，我们将创建一个适合捕获包含个体的流体液滴的矩阵 神经胶质和神经元细胞。该表面必须足够柔软，以最大程度地减少沉积过程中的细胞创伤和 必须鼓励这些细胞的生长并扩展其过程。由 脑外部成分透明质酸是开发此捕获的起点 基材。信号分子的嵌入将有助于指定细胞身份并鼓励细胞生长，并 矩阵属性的区域调制将有助于指导细胞组织。 其次，来自细胞分类技术的适应方法，我们将开发一个微流体系统的光学系统 细胞识别。当释放包含电池的液滴时，会施加电荷。当液滴掉落时 通过电压场，该电荷决定了其位置。这样，细胞将精确沉积 模式。 由 脑细胞 - 神经回路功能和病理学。考虑到涉及的神经系统疾病的巨大损失 海马，例如癫痫，抑郁和痴呆，改善了研究这些条件的手段 可能的治疗可能使数百万个人和家庭受益。确实，这个项目将提供一个 用于建造微生物生理系统的框架，以建模任何大脑电路。这有可能 为公共卫生带来显着价值。