Resolving the Role of Neuronal STING in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

解决神经元 STING 在肌萎缩侧索硬化症和额颞叶痴呆中的作用

基本信息

批准号：
10606865
负责人：
Clotilde Lagier-Tourenne
金额：
$ 208.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-05 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606865
关键词：
ALS pathology ALS patients Affect Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Behavioral Biological Markers Biological Process Brain C9ORF72 Clinic Collaborations Cre driver Cytoplasm DNA Damage Data Dementia Detergents Dipeptides Disease Disease Progression Disease model Frontotemporal Dementia Functional disorder Gene Activation Gene Expression Profile Genes Genetic Goals Human Individual Induced pluripotent stem cell derived neurons Innate Immune Response Interferon Type I Interferons Knock-out Link Location Massachusetts Mediating Microglia Modeling Molecular Motor Cortex Motor Neurons Mus Mutation Myelogenous Myeloid Cells Nerve Degeneration Neurites Neurodegenerative Disorders Neuroglia Neurons Parkinson Disease Pathologic Pathology Pathway interactions Phosphorylation Proteins Publishing RNA Research Role Signal Transduction Site Specific qualifier value Specificity Spinal Stimulator of Interferon Genes TDP-43 aggregation Temporal Lobe Testing Therapeutic Intervention Tissues Toxic effect Translation Initiation Translations Up-Regulation Vertebral column behavioral variant frontotemporal dementia cell type disorder control familial amyotrophic lateral sclerosis frontotemporal lobar dementia amyotrophic lateral sclerosis hippocampal pyramidal neuron immune activation improved in vitro Model in vivo induced pluripotent stem cell knock-down knockout gene mouse model neurodegenerative dementia neuronal survival neuropathology novel pathogen prevent primary outcome programs protein TDP-43 protein aggregation response secondary outcome skills sporadic amyotrophic lateral sclerosis stem cell model targeted treatment transcriptome sequencing

项目摘要

Project Summary: The stimulator of interferon genes (STING) pathway is responsible for sensing DNA damage and activating the innate immune response as part of a host pathogen defense program. Although STING has been implicated in several neurodegenerative diseases, the effect has thought to be mediated through myeloid cells, and the potential for STING activation within neurons has been not explored. The main goal of this proposal is to define the role of neuronal STING in neurodegeneration and dementia using amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in response to DNA damage. We will focus on the intronic hexanucleotide repeat in the C9orf72 gene, which is the most common familial cause of both ALS and FTD, and TDP-43, which aggregates in almost all ALS cases and about half of FTD. The overall model is that DNA damage, which can be caused by C9orf72 dipeptides as well as TDP-43 dysfunction, leads to STING activation in neurons. Our preliminary data present a concordant picture of increased neuronal STING in human C9orf72 brains, mouse C9orf72 models, and human induced pluripotent stem cell (iPSC)-derived neurons from ALS individuals. We will determine the regional specificity of STING increase and how it correlates with neurodegeneration, DNA damage, and other C9orf72 and TDP-43 disease features. To test the consequence of STING in neurons, we will use an AAV-based C9orf72 disease model and determine whether neuronal-specific knockout of STING affects neurodegeneration and how the effect compares to global knockout of STING or knockout within microglia. Using iPSC-derived and primary mouse neurons, we will determine mechanisms of STING activation, and how activation ties to downstream modulators within vulnerable neuronal subtypes. We will also assess to what extent blocking or knocking down STING protects neurons against disease mechanistic models in vitro. The successful completion of the project sets the stage for validating specific targets for therapeutic intervention, evaluating key pathway components as disease biomarkers, and investigating STING pathways in other neurodegenerative diseases and dementias.

项目概要：干扰素基因刺激器（STING）通路负责感知 DNA 作为宿主病原体防御程序的一部分，损害并激活先天免疫反应。尽管 STING 与多种神经退行性疾病有关，但人们认为其作用是通过骨髓细胞介导的，并且神经元内 STING 激活的潜力尚未被证实探索过。该提案的主要目标是定义神经元 STING 在神经退行性疾病中的作用和痴呆症使用肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）对DNA损伤的反应。我们将重点关注 C9orf72 基因中的内含子六核苷酸重复，这是 ALS 和 FTD 的最常见家族原因，而 TDP-43 则聚集在几乎所有 ALS 病例和大约一半的 FTD 病例。总体模型是DNA损伤，可以是由 C9orf72 二肽和 TDP-43 功能障碍引起的，导致神经元中 STING 激活。我们的初步数据呈现了人类 C9orf72 中神经元 STING 增加的一致图景大脑、小鼠 C9orf72 模型和人诱导多能干细胞 (iPSC) 衍生的神经元 ALS 个体。我们将确定 STING 增加的区域特异性及其与神经退行性变、DNA 损伤以及其他 C9orf72 和 TDP-43 疾病特征。测试 STING 对神经元的影响，我们将使用基于 AAV 的 C9orf72 疾病模型并确定 STING 的神经元特异性敲除是否会影响神经退行性变以及效果如何比较 STING 的全局敲除或小胶质细胞内的敲除。使用 iPSC 衍生的原代小鼠神经元，我们将确定 STING 激活的机制，以及激活如何与下游联系脆弱神经元亚型内的调节剂。我们还将评估阻止或阻止的程度敲除 STING 可保护神经元免受体外疾病机制模型的影响。成功者该项目的完成为验证治疗干预的具体目标奠定了基础，评估关键通路成分作为疾病生物标志物，并研究 STING 通路其他神经退行性疾病和痴呆症。