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.

项目概要阿尔茨海默病 (AD) 的病理标志包括淀粉样蛋白 -β (Aβ) 斑块的沉积和神经原纤维缠结中过度磷酸化的 Tau 聚集体的积累。被证明可以激活炎症小体信号传导。炎症小体是与炎症相关的先天免疫平台。许多慢性神经退行性疾病和炎症性疾病，例如 AD，正在被抑制。探索作为 AD 和其他复杂神经炎症/退行性疾病的治疗策略，包括最近的研究表明，帕金森病、多发性硬化症和年龄相关性黄斑变性（AMD）。确定了转座因子 (TE) 失调与 AD 之间的联系。一类 TE 的活性（短散布元件 (SINE)）在疾病发病机制中的机制作用 AMD 我们已经证明 SINE RNA 积累通过双重作用诱导 AMD 细胞变性。 NLRP3 和 NLRC4 炎性体的激活此外，我们还鉴定了 DDX17，一种 RNA 解旋酶，作为 SINE RNA 的分子传感器，可实现炎症小体的双重激活。初步研究已发现 5xFAD 中 Aβ 沉积物空间附近的 SINE RNA 失调 AD 模型以及 NLRC4-NLRP3 信号传导的新型小分子抑制剂可抑制炎症小体 Aβ 聚集体诱导的激活。尽管有这些发现，关于 AD 中的 SINE RNA 和炎症小体的知识仍然存在重大差距，例如，AD 中 SINE RNA 的细胞来源尚不清楚，SINE RNA 是否与 AD 相互作用并激活 AD 中的炎症小体成分尚不清楚，该提案将检验 AD 病理学的假设。 NLRP3/NLRC4 内源性 SINE RNA 积累诱导的激活会加剧这种情况，我们将对此进行测试。通过三个具体目标提出假设：1）我们将定量 SINE RNA 表达和炎性体激活，在 AD 的 5xFAD 模型中绘制它们的细胞起源；2) 我们将确定 SINE RNA-的细胞机制诱导脑小胶质细胞炎症小体激活，SINE RNA 是否通过影响 Aβ 吞噬作用小胶质细胞，以及炎性体抑制剂是否改善 Aβ 吞噬作用；以及 3）我们将测试其效果；单独和双重炎性体抑制剂对 Aβ 清除以及认知和行为缺陷的影响总的来说，这些主题相关但独立的目标将阐明 5xFAD 模型的贡献。 AD 中 SINE RNA 诱导的炎症小体激活该项目对 RFA-AG-22-021 具有响应性，因为它会 (a) (b) 定义 SINE RNA 与神经炎症之间的功能作用和因果关系； SINE RNA 的先天反应和免疫反应的机制；以及 (c) 测试治疗干预措施；这些研究将提供更深入的机制。了解 TE 的作用，可以作为未来转化研究的基础。