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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要为了减轻神经系统疾病的负担，诱导多能干细胞衍生的人脑细胞提供前所未有的洞察力的潜力。但神经系统的能力来自于相互作用其细胞，因此要将它们用作脑病理学模型，必须在它们的背景下对其进行研究可以像在体内一样相互影响。该领域需要具有建筑学的传真概括大脑回路的安排。研究对记忆至关重要且经常在疾病中发生改变的齿状回-海马 CA3 回路例如癫痫症，该项目将把神经元和神经胶质前体细胞放置在精确的位置。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液滴的矩阵神经胶质细胞和神经元细胞。该表面必须足够柔软，以尽量减少沉积和沉积过程中的细胞损伤必须促进这些细胞的生长及其过程的延伸。多孔支架由以下材料构成大脑细胞外成分透明质酸是该捕获开发的起点基材。信号分子的嵌入将有助于明确细胞身份并促进细胞生长，并且基质特性的区域调节将有助于指导细胞组织。其次，采用细胞分选技术的方法，我们将开发一种用于光学的微流控系统。细胞鉴定。当含有细胞的液滴被释放时，就会产生电荷。当水滴落下时通过电压场，该电荷决定其位置。通过这种方式，细胞将被精确地沉积在模式。由此产生的神经元和神经胶质细胞阵列将产生一个强大的、可重复的模型——由人类组成脑细胞——神经回路功能和病理学。鉴于涉及神经系统疾病的巨大损失海马体，如癫痫、抑郁症和痴呆症，改进了调查这些疾病的方法可能的治疗方法可以使数以百万计的个人和家庭受益。事实上，该项目将提供构建微生理系统以模拟任何大脑回路的框架。这有潜力对公共卫生产生重大价值。