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Validating cGAS-STING pathway as drug target in Huntington disease mouse model

在亨廷顿病小鼠模型中验证 cGAS-STING 通路作为药物靶点

基本信息

批准号：
10508092
负责人：
Srinivasa Subramaniam
金额：
$ 53.13万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508092
关键词：
Address Affect Amyotrophic Lateral Sclerosis Anatomy Animal Diseases Anti-Inflammatory Agents Atrophic Autophagocytosis Behavioral Body Weights and Measures CAG repeat Catabolic Process Cell Culture Techniques Cell model Cells Clinical Trials Code Corpus Callosum Corpus striatum structure Cyclic GMP Data Defect Development Disease Disease Progression Disease model Drug Targeting Etiology Exons Functional disorder Gene Activation Genes Genetic Genetic Transcription Human Huntington Disease Huntington gene Immunohistochemistry Impaired cognition Inflammation Inflammatory Inflammatory Response Knock-in Mouse Knock-out Knockout Mice Knowledge Kynurenine Link Mediating Messenger RNA Microglia Mission Modeling Modification Molecular Monkey Diseases Motor Motor Activity Mus Mutation Natural Immunity Nerve Degeneration Neurodegenerative Disorders Onset of illness Pain Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Performance Peripheral Persons Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Public Health Research Research Personnel Ribosomes Role Severity of illness Signal Pathway Signal Transduction Stimulator of Interferon Genes Symptoms Techniques Testing Therapeutic Therapeutic Agents Time Tissue Model Tissues Tryptophan United States National Institutes of Health Walking Western Blotting Work age related base brain tissue chemokine cytokine disability disease phenotype effective therapy experimental study inhibitor insight intraperitoneal monocyte mouse model mutant nervous system disorder novel novel therapeutic intervention polyglutamine pre-clinical prevent response small molecule small molecule inhibitor targeted treatment therapeutic target transcription factor transcriptome sequencing

项目摘要

Project summary Huntington disease (HD) is a fatal neurodegenerative disorder caused by the huntingtin (HTT) CAG expansion mutation (coding for polyglutamine, mHTT). mHTT is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. Prior works have linked innate and adaptive inflammatory responses in HD. Microglia, a cellular indicator of inflammation, is also increased in the striatum of HD animal and cell culture models and HD patients. Increased levels of reactive monocytes, inflammatory cytokines, chemokines, and the n-kynurenine/tryptophan ratio, an indicator of persistent inflammation, have all been observed in pre-manifest HD patients and correlated with HD progression. Furthermore, RNA-seq analysis of tissue obtained from human HD patients and HD monkey models reveals extensive transcriptional dysregulation associated with proinflammatory pathway activation. Inflammation is also closely linked to autophagy, a catabolic process that is dysregulated in HD. Despite these studies, the mechanisms or treatment targets for the reduction of inflammatory responses remain less clear. To fill this knowledge gap, this proposal tests the hypothesis that cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING), a major innate immunity response pathway, is a disease modifier in HD pathogenesis. This hypothesis was formulated based on our recent finding that the cGAS-STING pathway is upregulated in HD patients’ tissue and cell models and mediates autophagy and inflammatory responses. We found high ribosome occupancy in exon 1 of cGAS mRNA and cGAS-dependent inflammatory transcription factors (Irf3, Irf7), and inflammatory chemokine (Ccl5, and Cxcl10) are upregulated in HD. Depletion of cGAS diminishes downstream effector STING activation and also inhibits autophagy flux in HD cells. The latter is consistent with the primordial function of the cGAS-STING pathway in autophagy induction. These data underline an important role of cGAS-STING signaling in the pathological mechanisms of HD. Subsequently, an independent study confirmed activation of cGAS-STING in HD models. Yet, it is unclear whether the cGAS- STING pathway is a passive or active contributor to HD development. In Aim 1, we will determine whether the genetic deletion of cGAS alters the behavioral and pathological hallmarks of HD KI (z175HD) mice. We will determine age-related behavioral alterations and pathological changes in cGAS–/–;HD KI mice. In Aim 2, we will determine whether the small molecule STING inhibitor diminishes the HD phenotype in HD KI mice. We will treat z175HD mice with the small molecule STING inhibitor, H-151 and determine changes in the HD-like deficits compared vehicle treated z175HD. The proposed experiments will clarify the role of the cGAS–STING pathway as anti-inflammatory therapeutic agents in HD.

项目摘要亨廷顿病（Huntington disease，HD）是由亨廷顿蛋白（huntingtin，HTT）CAG扩增引起的一种致死性神经退行性疾病突变（编码多聚谷氨酰胺，mHTT）。mHTT是一种普遍表达的基因，但它显著损害纹状体和皮质，随着疾病的进展，随之而来的是广泛的外周缺陷。之前的作品有先天性和适应性炎症反应相关。小胶质细胞是炎症的细胞指标，在HD动物和细胞培养模型以及HD患者的纹状体中增加。反应水平增加单核细胞，炎性细胞因子，趋化因子和n-犬尿氨酸/色氨酸比率，持续性炎症，均在表现前HD患者中观察到，并与HD进展相关。此外，从人HD患者和HD猴模型获得的组织的RNA-seq分析揭示了与促炎通路激活相关的广泛转录失调。炎症也是与自噬密切相关，自噬是HD中失调的分解代谢过程。尽管有这些研究，减少炎症反应的机制或治疗靶点仍然不太清楚。填补这一知识差距，这项建议测试的假设，环GMP-AMP合酶（cGAS）-刺激剂的干扰素基因（STING）是一种主要的先天免疫反应途径，是HD的疾病修饰因子发病机制这一假设是基于我们最近的发现，即cGAS-STING途径是在HD患者的组织和细胞模型中上调，并介导自噬和炎症反应。我们发现cGAS mRNA和cGAS依赖性炎症转录的外显子1中存在高核糖体占据率因子（Irf 3、Irf 7）和炎性趋化因子（Ccl 5和Cxcl 10）在HD中上调。cGAS消耗减少下游效应STING活化，并且还抑制HD细胞中的自噬通量。后者是这与cGAS-STING途径在自噬诱导中的原始功能一致。这些数据表明， cGAS-STING信号在HD病理机制中的重要作用。随后拟订一项独立研究证实了cGAS-STING在HD模型中的活化。目前尚不清楚cGAS是否... STING途径是HD发展的被动或主动贡献者。在目标1中，我们将确定 cGAS的遗传缺失改变了HD KI（z175 HD）小鼠的行为和病理学特征。我们将确定cGAS-/-;HD KI小鼠中年龄相关的行为改变和病理学变化。在目标2中，我们将确定小分子STING抑制剂是否减少HD KI小鼠中的HD表型。本公司对待用小分子STING抑制剂H-151处理z175 HD小鼠，并确定HD样缺陷的变化比较媒介物处理的z175 HD。拟议的实验将阐明cGAS-STING途径的作用作为HD的抗炎治疗剂。