Developing astrocyte, neuron, and microglial 3D organoids to model key aspects of human pathology

开发星形胶质细胞、神经元和小胶质细胞 3D 类器官来模拟人类病理学的关键方面

基本信息

批准号：
9899912
负责人：
Erik M Ullian
金额：
$ 16.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899912
关键词：
3-Dimensional Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Astrocytes Biological Biology Blood flow Brain Buffers CRISPR interference Cell physiology Cells Clustered Regularly Interspaced Short Palindromic Repeats Complement Complement 4b Complex Dementia Developmental Biology Disease Drug Targeting Foundations Future GRN gene Gene Activation Gene Expression Genes Goals Homeostasis Human Human Pathology Immune Ions Knock-out Lead Link Lobular Measures Metabolic Microglia Modeling Molecular Morphology Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Ceroid-Lipofuscinosis Neurons Neurotransmitters Nuclear Organoids PGRN gene Pathology Pathway interactions Patients Phenotype Play Proteins Research Rodent Rodent Model Role Signal Pathway Signal Transduction Stress Synapses Synaptic Transmission Synaptic plasticity System TDP-43 aggregation Temporal Lobe Testing Work age related neurodegeneration base cell type complement pathway experimental study extracellular gene complementation genome wide association study glial activation granulin healthy aging hippocampal sclerosis human model induced pluripotent stem cell insight interest knock-down neuron loss neuronal survival neurotoxic novel overexpression prevent protein TDP-43 protein aggregation three dimensional cell culture tool transcription factor translational study

项目摘要

Project Summary Astrocytes are the most abundant non-neuronal cell types in the brain. Astrocytes promote neuronal survival, provide neurons with metabolic substrates, help recycle synaptic neurotransmitters, regulate blood flow, buffer extracellular ions, induce or eliminate synapses and regulate synaptic transmission and synaptic plasticity. Most recently, it has been shown that when specific signaling pathways are compromised, astrocytes can become reactive and can start eliminating synapses ultimately; leading to neuronal cell death during both natural aging and age-related neurodegenerative diseases. Our research aims to understand how astroglial activation is initiated in Alzheimer’s Disease (AD). We will focus on this question by studying a gene called granulin (GRN). This gene has been linked to aging in the human cortex and loss of GRN inevitably leads to astroglial activation and a devastating neurodegenerative disease termed Frontal Temporal Lobar Degeneration (FTLD). To begin to tackle this question, we propose investigating the molecular mechanisms of GRN signaling on astroglial activation. The goal of our work is to understand how normal GRN function prevents protein mislocalization in healthy aging human neurons, and how loss of GRN causes these same proteins to mislocalize in neurons: leading to neuronal death in AD and FTLD. Based on recent findings that rodent astrocytes and human astrocytes are genetically and morphologically very different, we will use human cells to study this question and set up a novel 3D human induced pluripotent stem cell (iPSC) organoid system to incorporate human neurons, astrocytes and microglia. We will then analyze the mislocalization of specific protein in GRN positive and GRN knockout organoids. We will also study the signaling differences between GRN positive and GRN knockout astrocytes, and focus on the innate immune complement pathway and how GRN affects this pathway. Collectively, these studies will allow us to identify the factors in astrocytes that promote brain homeostasis, aging and disease.

项目概要星形胶质细胞是大脑中最丰富的非神经元细胞类型，可促进神经元存活。为神经元提供代谢底物，帮助回收突触神经递质，调节血流，缓冲细胞外离子，诱导或消除突触并调节突触传递和突触可塑性。最近，研究表明，当特定信号通路受到损害时，星形胶质细胞可以变得反应性并最终开始消除突触，导致神经元细胞死亡；我们的研究旨在了解星形胶质细胞如何影响自然衰老和与年龄相关的神经退行性疾病。激活是在阿尔茨海默病 (AD) 中启动的，我们将通过研究一个名为“AD”的基因来关注这个问题。该基因与人类皮质的衰老有关，GRN 的丧失不可避免地会导致衰老。星形胶质细胞激活和一种称为额颞叶的破坏性神经退行性疾病为了开始解决这个问题，我们建议研究其分子机制。 GRN 信号对星形胶质细胞激活的影响我们工作的目标是了解正常的 GRN 功能如何。防止蛋白质在健康老化的人类神经元中错误定位，以及 GRN 的缺失如何导致这些错误蛋白质在神经元中错误定位：导致 AD 和 FTLD 中的神经元死亡。啮齿动物星形胶质细胞和人类星形胶质细胞在遗传和形态上有很大不同，我们将使用人类星形胶质细胞细胞来研究这个问题并建立一个新型的 3D 人类诱导多能干细胞 (iPSC) 类器官系统然后我们将分析特定神经元、星形胶质细胞和小胶质细胞的错误定位。我们还将研究 GRN 阳性和 GRN 敲除类器官中的蛋白质。 GRN 阳性和 GRN 敲除星形胶质细胞，重点关注先天免疫补体途径以及如何总的来说，这些研究将使我们能够确定星形胶质细胞中影响该通路的因素。促进大脑稳态、衰老和疾病。