Role of R-loops in transcriptional stress, genome instability, and chronic immune response in Alzheimer's disease

R 环在阿尔茨海默病转录应激、基因组不稳定性和慢性免疫反应中的作用

• 批准号: 10807585
• 负责人: Hana Hall
• 金额: $ 49.13万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807585
• 关键词: Acceleration; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Autopsy; Basic Science; Blindness; Brain; Chronic; Chronic Disease; Clinical; Cytoplasm; DNA; DNA Damage; Data; Defect; Dementia; Development; Drosophila genus; Drosophila melanogaster; Elderly; Epigenetic Process; Eukaryota; Exogenous Factors; Functional disorder; Gene Expression; Genetic Transcription; Genome; Genomic Instability; Health; Hippocampus; Homeostasis; Human; Hybrids; Immune response; Impairment; In Vitro; Incidence; Individual; Inflammation; Inflammatory Response; Late Onset Alzheimer Disease; Lead; Link; Methyltransferase; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Pathology; Pathway interactions; Patients; Process; RNA; RNA metabolism; RNA methylation; Rattus; Reporting; Research; Research Proposals; Resistance; Resolution; Risk Factors; Role; Single-Stranded DNA; Stress; Symptoms; System; Therapeutic; Toxic effect; Vision; age related; age related neurodegeneration; biological adaptation to stress; epitranscriptomics; genomic locus; model organism; mouse model; nervous system disorder; neuroinflammation; novel; novel therapeutic intervention; nucleic acid structure; posttranscriptional; tau Proteins; tau aggregation

Advanced age is a major risk factor for many chronic diseases, including Alzheimer’s disease (AD). Despite substantial research progress, most treatments currently available merely mitigate symptoms. Given that most of patients with dementia due to AD are sporadic, and in those, aging is the key risk factor for this late-onset AD, targeting the mechanisms that have been collectively summarized as “hallmarks of aging” may provide avenues for development of new therapeutic approaches. Emerging evidence links aging and age-related neurodegenerative diseases to disruption in RNA alterations, specifically N6-methyladenosine (m6A) modification. m6A RNA is the most prevalent and abundant modification of RNA in eukaryotes, with high expression specifically in the brain. Recently, m6A RNA has been shown to regulate stability of R-loops; three- nucleic acid structures, consisting of an RNA-DNA hybrid and a ssDNA that form during transcription. In this proposal we will examine the role of m6A epi-transcriptomic modification in R-loop-driven pathophysiology of AD. Using Drosophila AD model, in aim 1 we will elucidate how m6A RNA impairment impacts R-loop distribution across the genome and formation of RNA-DNA hybrids in cytoplasm, and their impact on transcriptional stress and activation of chronic immune response in AD. The significance of aim 2 is in identifying the regulatory mechanisms of R-loop-dependent DSB formation in AD. While variety of exogenous factors can contribute to DNA damage, we will define a role of R-loops in genome instability associated with AD. Moreover, we will define the epigenetic modifications associated with formation of stable R-loops resistant to resolution, which are alternatively processed into DSBs. In aim 3, we will expand our studies from Drosophila to mammalian system. Using in vitro rat cortical neuron cultures seeded with human brain tau, we will further elucidate the molecular mechanisms of R-loop associated genome instability and neuroinflammation in AD. Neurons have specialized RNA metabolism and it is therefore not surprising that dysfunction in RNA metabolism is strongly associated with neurological diseases. This proposal focuses on a novel possibility that defects in RNA metabolism, and particularly R-loop homeostasis, is a significant driver of transcriptional stress, genome instability, and chronic immune response; key hallmarks of aging, whose acceleration may lead to neurodegeneration.

高龄是许多慢性病的主要风险因素，包括阿尔茨海默病(AD)。尽管 尽管取得了实质性的研究进展，但目前可用的大多数治疗方法只是减轻了症状。考虑到最大的 AD引起的痴呆症患者中有零星的，而在这些患者中，衰老是这种迟发性AD的关键危险因素， 针对已被集体总结为“老龄化标志”的机制可能会提供途径 用于开发新的治疗方法。新出现的证据表明老龄化与年龄相关 神经退行性疾病导致RNA改变中断，特别是N6-甲基腺苷(M6A) 修改。M6A RNA是真核生物中最普遍、最丰富的RNA修饰形式，具有高度的 特别是在大脑中的表达。最近，m6A RNA被证明可以调节R环的稳定性； 核酸结构，由RNA-DNA杂交体和在转录过程中形成的单链DNA组成。 在这项提案中，我们将研究m6A表转录修饰在R环驱动的病理生理学中的作用 公元一代的。利用果蝇AD模型，在目标1中，我们将阐明m6A RNA损伤如何影响R-环 在基因组中的分布和细胞质中RNA-DNA杂交体的形成及其对 转录应激与阿尔茨海默病慢性免疫反应的激活目标2的意义在于确定 AD中依赖R环的DSB形成的调控机制。而各种外生因素可以 导致DNA损伤，我们将定义R-环在与AD相关的基因组不稳定性中的作用。此外， 我们将定义与形成稳定的抵抗分辨的R-环相关的表观遗传修饰， 它们被交替地加工成DSB。在目标3中，我们将把我们的研究从果蝇扩展到哺乳动物 系统。利用体外培养的含有人脑tau蛋白的大鼠皮质神经元，我们将进一步阐明 阿尔茨海默病R环相关基因组不稳定性和神经炎症的分子机制。神经元有 专门化的RNA新陈代谢，因此毫不奇怪，RNA新陈代谢功能障碍严重 与神经系统疾病有关。 这项建议侧重于一种新的可能性，即RNA新陈代谢的缺陷，特别是R环 动态平衡，是转录应激、基因组不稳定和慢性免疫反应的重要驱动因素； 衰老的关键特征，其加速可能导致神经退化。