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Novel AAV Capsids and Gene Regulatory Elements for GeneExpression in Microglia

用于小胶质细胞基因表达的新型 AAV 衣壳和基因调控元件

基本信息

批准号：
10195876
负责人：
Benjamin E Deverman
金额：
$ 24万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195876
关键词：
ATAC-seq Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Automobile Driving Binding Blood - brain barrier anatomy Brain Brain Diseases Capsid Cell Nucleus Cell surface Cells Chromatin Code Communities DNA Data Degradation Pathway Dependovirus Development Disease Elements Engineering Enzymes Exhibits Gene Expression Genes Genetic study Genome Goals Immunohistochemistry In Situ Hybridization In Vitro Individual Injections Label Late Onset Alzheimer Disease Lentivirus Libraries Link Mediating Microglia Mus Neurosciences Neurosciences Research Outcome Play Publishing RNA Rare Diseases Regulator Genes Regulatory Element Resistance Role Safety Schizophrenia Slice Synapses Testing Time Transgenic Animals Transgenic Mice Variant Viral Viral Genome Viral Vector Virus Work adeno-associated viral vector blood-brain barrier crossing brain cell cell type complement system gene therapy human embryonic stem cell improved in vivo in vivo evaluation inhibitor/antagonist macrophage novel particle prevent protein degradation risk variant tool trafficking transgene expression vector genome

项目摘要

Project Summary: Microglia, the resident macrophages of the brain, assume a multitude of functions during brain development and disease. Long known to react to changes in brains affected by Alzheimer’s disease (AD), genetic studies of late- onset AD indicate that AD risk variants are commonly found in or near genes that are specifically expressed in microglia, suggesting that microglia play an active role in driving AD. In addition, microglia exhibit various functions during brain development, including synapse pruning. Genes coding for components of the complement system, which mediates synapse pruning by microglia, have been linked to schizophrenia. However, a major bottleneck in studying the roles of microglia in normal and diseased brains is the lack of viral tools for rapidly manipulating their gene expression. Viral vectors would also benefit studies where transgenic animals are not available. Finally, viral vectors would enable studies on the potential of gene therapy for AD and rare diseases that affect microglia. However, while microglia show modest and localized transduction by lentiviruses in vivo, they are resistant to transduction by adeno-associated viruses (AAVs), the preferred viral vectors used in neuroscience research and gene therapy due to their superior spread and excellent safety profile. Here we propose to elucidate the barriers to microglia transduction by AAVs, engineer AAV capsid variants that are able to overcome these barriers and transduce microglia in vivo, and develop novel gene regulatory elements that will enable microglia-specific transgene expression from viral vectors. This will be a collaborative project between the Stevens and Deverman labs, combining their expertise in studying microglia (Stevens) and in developing novel AAV vectors (Deverman).

项目摘要：小胶质细胞是大脑的常驻巨噬细胞，在大脑发育期间承担多种功能，疾病长期以来，人们都知道阿尔茨海默病（AD）会对大脑的变化做出反应，最近的遗传研究表明， AD发作表明AD风险变异体通常存在于或接近于在AD中特异性表达基因中，小胶质细胞，表明小胶质细胞在驱动AD中发挥积极作用。此外，小胶质细胞表现出各种大脑发育过程中的功能，包括突触修剪。基因编码的组成部分，通过小胶质细胞介导突触修剪的补体系统与精神分裂症有关。然而，研究小胶质细胞在正常和患病大脑中的作用的一个主要瓶颈是缺乏病毒表达。快速操纵基因表达的工具。病毒载体也将有利于转基因的研究，没有动物可用。最后，病毒载体将使研究基因治疗AD的潜力成为可能，影响小胶质细胞的罕见疾病。然而，虽然小胶质细胞显示出适度的和局部的转导，在体内，它们对腺相关病毒（AAV）的转导具有抗性，优选的腺相关病毒（AAV）是慢病毒。由于它们的上级扩散性和极好的安全性，它们被用于神经科学研究和基因治疗。在这里，我们建议阐明AAV对小胶质细胞转导的障碍，工程化AAV衣壳变体，能够克服这些障碍，在体内抑制小胶质细胞，并开发新的基因调控元件，这将使病毒载体能够表达小胶质细胞特异性转基因。这将是一个合作项目史蒂文斯和德弗曼实验室之间，结合他们在研究小胶质细胞（史蒂文斯）和开发新的AAV载体（Deverman）。