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.

高龄是许多慢性疾病的主要危险因素，包括阿尔茨海默病（AD）。尽管 随着大量研究的进展，目前可用的大多数治疗方法仅能减轻症状。鉴于大多数 的AD所致痴呆患者是散发性的，在这些患者中，衰老是这种迟发性AD的关键风险因素， 针对那些被统称为“衰老标志”的机制， 用于开发新的治疗方法。新出现的证据将衰老与年龄相关 神经退行性疾病对RNA改变的破坏，特别是N6-甲基腺苷（m6 A） 改性m6 A RNA是真核生物中最普遍和最丰富的RNA修饰， 特别是在大脑中。最近，m6 A RNA已被证明可以调节R环的稳定性;三个- 核酸结构，由RNA-DNA杂交体和在转录过程中形成的ssDNA组成。 在这个提议中，我们将研究m6 A表观转录组修饰在R环驱动的病理生理学中的作用。 的AD。利用果蝇AD模型，在目标1中，我们将阐明m6 A 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，以及它们对 转录应激和激活AD中的慢性免疫应答。目标2的意义在于确定 AD中R环依赖性DSB形成的调节机制。虽然各种外部因素可以 有助于DNA损伤，我们将定义与AD相关的基因组不稳定性中的R环的作用。此外，委员会认为， 我们将定义与形成抵抗分解的稳定R环相关的表观遗传修饰， 它们被交替地处理成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 系统使用体外大鼠皮层神经元培养接种人脑tau蛋白，我们将进一步阐明 AD中R环相关基因组不稳定性和神经炎症的分子机制。神经元具有 因此，RNA代谢的功能障碍在RNA代谢中的强烈表达并不奇怪。 与神经系统疾病有关。 这项提案集中在一个新的可能性，缺陷的RNA代谢，特别是R-环 稳态，是转录应激、基因组不稳定性和慢性免疫应答的重要驱动因素; 衰老的关键标志，其加速可能导致神经退化。