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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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）。实质性的研究进展，目前大多数可用的治疗方法只是缓解症状。因 AD 导致的痴呆症患者是散发性的，在这些患者中，衰老是这种迟发性 AD 的关键危险因素，针对被统称为“衰老标志”的机制可能提供途径开发新的治疗方法。神经退行性疾病导致 RNA 改变受到破坏，特别是 N6-甲基腺苷 (m6A) m6A RNA 修饰是真核生物中最普遍、最丰富的 RNA 修饰。最近，m6A RNA 已被证明可以调节 R 环的稳定性；核酸结构，由 RNA-DNA 杂合体和转录过程中形成的 ssDNA 组成。在本提案中，我们将研究 m6A 表观转录组修饰在 R 环驱动的病理生理学中的作用使用果蝇 AD 模型，在目标 1 中，我们将阐明 m6A RNA 损伤如何影响 R 环整个基因组的分布和细胞质中 RNA-DNA 杂交体的形成，及其对 AD 中的转录应激和慢性免疫反应的激活目标 2 的意义在于识别。 AD 中 R 环依赖性 DSB 形成的调节机制，而多种外源因素可以。导致 DNA 损伤，我们将定义 R 环在 AD 相关基因组不稳定中的作用。我们将定义与形成抗解析的稳定 R 环相关的表观遗传修饰，或者将其加工成 DSB 在目标 3 中，我们将把我们的研究范围从果蝇扩展到哺乳动物。使用接种人脑 tau 的体外大鼠皮质神经元培养物，我们将进一步阐明该系统。 AD 中 R 环相关基因组不稳定和神经炎症的分子机制。专门的 RNA 代谢，因此，RNA 代谢功能障碍强烈地影响也就不足为奇了。与神经系统疾病有关。该提案重点关注 RNA 代谢缺陷（尤其是 R 环）的一种新可能性体内平衡是转录应激、基因组不稳定和慢性免疫反应的重要驱动因素；衰老的关键标志，其加速可能导致神经退行性变。