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Defining the role of SINE retrotransposons and inflammasome activation in Alzheimer's disease

定义 SINE 逆转录转座子和炎症小体激活在阿尔茨海默病中的作用

基本信息

批准号：
10696066
负责人：
Jayakrishna Ambati
金额：
$ 62.08万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2022-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696066
关键词：
Abeta clearance Age related macular degeneration Aging Alu Elements Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Anatomy Animal Disease Models Animal Model Behavioral Brain CASP1 gene Cells Characteristics Chronic Cicatrix Cognitive Complex DNA Transposable Elements Degenerative Disorder Deposition Development Elements Epidemiology Eye Foundations Future Genetic Genetic Transcription Genome Human Human Characteristics Human Genome IL18 gene Immune Immune response Immune signaling Immunology Impairment Individual Inflammasome Inflammation Inflammatory Interleukin-1 beta Knowledge Licensing Link Maps Mediating Microglia Modeling Molecular Multiple Sclerosis Mus Nerve Degeneration Neurofibrillary Tangles Nuclear Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phagocytosis Phosphorylation Proteins RNA RNA Helicase RNA Polymerase III Retrotransposition Retrotransposon Role Science Senile Plaques Short Interspersed Nucleotide Elements Signal Pathway Signal Transduction Source Structure of retinal pigment epithelium Techniques Testing Therapeutic Therapeutic Intervention Toxic effect Transcript Translational Research Visualization abeta accumulation abeta deposition age related neurodegeneration brain cell cell type cognitive function cytokine cytotoxicity efficacy testing functional outcomes genetic element hyperphosphorylated tau immune activation improved inhibitor mouse genome mouse model neuroinflammation novel pharmacologic progressive neurodegeneration protein aggregation sensor small molecule inhibitor spatiotemporal targeted treatment tau Proteins tau aggregation therapeutic evaluation

项目摘要

PROJECT SUMMARY Pathological hallmarks of Alzheimer's disease (AD) include deposition of Amyloid-β (Aβ) plaques and accumulation of hyperphosphorylated Tau aggregates in neurofibrillary tangles. These aggregates have been demonstrated to activate inflammasome signaling. Inflammasomes are innate immune platforms implicated in numerous chronic neurodegenerative and inflammatory conditions such as AD. Inflammasome inhibition is being explored as a therapeutic strategy for AD and other complex neuroinflammatory/degenerative disorders including Parkinson's disease, multiple sclerosis, and age-related macular degeneration (AMD). Recent studies have identified links between dysregulation of transposable elements (TEs) and AD. We have established a critical mechanistic role for activity of one class of TEs – short interspersed elements (SINEs) – in the pathogenesis of AMD. We have demonstrated that SINE RNA accumulation induces cellular degeneration in AMD by dual activation of the NLRP3 and NLRC4 inflammasomes. Furthermore, we have identified DDX17, an RNA helicase, as the molecular sensor of SINE RNAs that licenses dual activation of the inflammasomes. Moreover, our preliminary studies have identified dysregulation of SINE RNAs in spatial proximity to Aβ deposits in the 5xFAD model of AD and that a novel small molecule inhibitor of NLRC4-NLRP3 signaling suppresses inflammasome activation induced by Aβ aggregates. Notwithstanding these findings, major gaps in knowledge about SINE RNAs and inflammasomes in AD persist, e.g, the cellular sources of SINE RNAs in AD are undefined and whether SINE RNAs interact with and activate inflammasome components in AD is unknown. This proposal will test the hypothesis that AD pathology is exacerbated by NLRP3/NLRC4 activation induced by endogenous SINE RNA accumulation. We will test this hypothesis via three specific aims: 1) We will quantitate SINE RNA expression and inflammasome activation and map their cellular origins in the 5xFAD model of AD; 2) We will determine the cellular mechanisms of SINE RNA- induced inflammasome activation in brain microglia, whether SINE RNA compromises Aβ phagocytosis by microglia, and whether inflammasome inhibitors improve Aβ phagocytosis; and 3) We will test the effects of individual and dual inflammasome inhibitors on Aβ clearance as well as cognitive and behavioral deficits in the 5xFAD model. Collectively, these thematically related but independent aims will shed light on the contribution of SINE RNAs-induced inflammasome activation in AD. This project is responsive to RFA-AG-22-021 as it will (a) define the functional roles and causal relationships between SINE RNAs and neuroinflammation; (b) define the mechanisms underpinning innate and immune responses to SINE RNAs; and (c) test therapeutic interventions interfering with SINE RNA-mediated molecular pathways. These studies will provide a deeper mechanistic understanding of the role of TEs that can serve as a foundation for future translational research.

项目摘要阿尔茨海默病（AD）的病理学标志包括淀粉样蛋白-β（A β）斑块的沉积和过度磷酸化的Tau聚集体在神经元缠结中的积累。这些聚合物已经证实激活炎性体信号传导。炎性小体是先天免疫平台，许多慢性神经退行性和炎症性疾病，如AD。炎性小体抑制正在被探索作为AD和其他复杂神经炎症/退行性疾病的治疗策略，包括帕金森病、多发性硬化症和年龄相关性黄斑变性（AMD）。最近的研究确定了转座因子（TE）失调与AD之间的联系。我们已经建立了一个关键的一类TE-短散在元件（SINE）-的活性在发病机制中的机械作用 AMD.我们已经证明，SINE RNA的积累诱导细胞变性AMD的双重作用， NLRP 3和NLRC 4炎性体的活化。此外，我们已经鉴定了DDX17，一种RNA解旋酶，作为SINE RNA的分子传感器，允许炎性小体的双重激活。而且我们初步研究已经确定了5xFAD中与A β沉积物空间接近的SINE RNA的失调 AD模型和NLRC4-NLRP3信号传导的新型小分子抑制剂抑制炎性小体 A β聚集体诱导的活化。尽管有这些发现，关于AD中SINE RNA和炎性小体的知识仍然存在重大差距，例如，AD中SINE RNA的细胞来源是不确定的， AD中的炎性小体组分是未知的。该提案将检验AD病理学是通过内源性SINE RNA积累诱导的NLRP 3/NLRC 4活化而加剧。我们将测试这个通过三个特定的目的进行假设：1）我们将定量SINE RNA表达和炎性小体活化，在AD的5xFAD模型中绘制它们的细胞起源; 2）我们将确定SINE RNA的细胞机制- 在脑小胶质细胞中诱导炎性小体活化，SINE RNA是否通过小胶质细胞，以及炎性小体抑制剂是否改善A β吞噬作用;以及3）我们将测试单个和双重炎性体抑制剂对A β清除以及认知和行为缺陷的影响 5xFAD型号。总的来说，这些主题相关但独立的目标将揭示以下方面的贡献： AD中SINE RNA诱导的炎性小体活化。本项目响应RFA-AG-22 - 021，因为它将（a）定义SINE RNA和神经炎症之间的功能作用和因果关系;（B）定义SINE RNA和神经炎症之间的功能作用和因果关系; 支持对SINE RNA的先天和免疫应答的机制;以及（c）测试治疗干预干扰SINE RNA介导的分子途径。这些研究将提供更深层次的机制了解TE的作用，可以作为未来翻译研究的基础。