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氏病（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的高磷酸化tau聚集体的积累。这些骨料已经证明可以激活炎症体信号传导。炎症是实施的先天免疫平台许多慢性神经退行性和炎症状况，例如AD。炎性抑制正在作为AD和其他复杂神经炎症/退化性疾病的治疗策略探索帕金森氏病，多发性硬化症和与年龄相关的黄斑变性（AMD）。最近的研究鉴定的转座元素（TES）和AD的失调之间的联系。我们已经建立了关键一类TE的活性的机械作用 - 短散布元素（罪） - 在发病机理中 AMD。我们已经证明，正弦RNA的积累可通过双重诱导AMD中的细胞变性 NLRP3和NLRC4炎症的激活。此外，我们已经确定了DDX17，一种RNA解旋酶，作为正弦RNA的分子传感器，该传感器获得了炎症双重激活的许可。而且，我们的初步研究已经确定了在5xFAD中与Aβ沉积物的空间邻近中正弦RNA的失调 AD的模型和NLRC4-NLRP3信号传导的新型小分子抑制剂抑制了炎症体 Aβ聚集体诱导的激活。尽管有这些发现，但关于正弦RNA和AD炎症的知识差距很大，例如，AD中正弦RNA的细胞来源不确定，正弦RNA是否与和激活相互作用 AD中的炎性组成分尚不清楚。该建议将检验AD病理学的假设由内源正弦RNA积累诱导的NLRP3/NLRC4激活加剧。我们将测试这个通过三个特定目的的假设：1）我们将定量正弦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）我们将确定正弦RNA-的细胞机制诱发脑小胶质细胞中的炎性体激活，正弦RNA是否会损害Aβ吞噬作用小胶质细胞，以及炎性抑制剂是否改善Aβ吞噬作用； 3）我们将测试 Aβ清除率以及认知和行为的个体和双重炎症抑制剂在 5XFAD模型。总的来说，这些主题相关但独立的目标将阐明正弦RNA诱导的AD炎性体激活。该项目对RFA-AG-22-021响应（a）定义正弦RNA与神经炎症之间的功能作用和因果关系；（b）定义基于对正弦RNA的先天和免疫反应的机制；（c）测试治疗干预措施干扰正弦RNA介导的分子途径。这些研究将提供更深的机械了解TE的作用，可以作为未来翻译研究的基础。