A Forgotten Connection: Retrotransposon contribution to Alzheimer's Disease

被遗忘的联系：逆转录转座子对阿尔茨海默病的贡献

• 批准号: 10288552
• 负责人: Victoria Perepelitsa Belancio
• 金额: $ 37.48万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-18 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288552
• 关键词: Administrative Supplement; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Area; Brain; Case-Control Studies; Cerebral cortex; DNA; DNA Damage; Dementia; Detection; Development; Etiology; Funding; Genetic; Genetic Transcription; Genome; Genomics; Goals; Hippocampus (Brain); Impaired cognition; Individual; Legal patent; Mediating; Methods; Molecular; Neurofibrillary Tangles; Neurons; Outcome; Play; Prognostic Marker; Proteins; Research; Retrotransposition; Retrotransposon; Risk; Role; Testing; age related; epigenetic silencing; human DNA; improved; neuron loss; pre-clinical; promoter; therapy development

One goal of the existing R01 is the development of a high throughput method, called SCORE, for detection of polymorphic L1s (pL1s) retrotransposons in human DNA. Our existing R01 does not include any studies involving analysis of Alzheimer's Disease (AD) patents' genomes. However, such analysis would be within the scope of this R01 because pL1s and their DNA damage are a common theme of both the funded R01 and the proposed Administrative Supplement. The proposed research is important to AD because brains of AD patients have increased levels of DNA breaks compared to age-matched controls with evidence supporting that this damage leads to neuronal loss at the pre-clinical stage of AD when plaques and tangles have not yet been formed. Thus, identification of an additional mechanism(s) underlying neuronal loss will significantly improve our understanding of AD etiology and progress in treatment development. Several molecular mechanisms guard against L1-associated damage. One of them is a TRIM28-mediated suppression of L1 expression by epigenetic silencing of L1 promoters. Although TRIM28 is expressed in neurons throughout the brain, L1 damage occurs in hippocampus and cerebral cortex, which are the areas that are also affected in AD patients. Our preliminary findings show that, independent of its role in suppression of L1 transcription, TRIM28 interacts with L1 proteins and stimulates L1 retrotransposition. We hypothesize that genomes of AD patients have more pL1s than genomes of normal subjects, which can contribute to the neuronal loss associated with an increase in L1-associated DNA damage, especially when combined with deregulation of TRIM28. We will test our hypothesis through two specific aims. Aim 1 will perform a case-control study to determine the number of pL1s in the genomes of AD patients (case) and age-matched subjects without cognitive impairment (control). This aim will determine whether the number and/or composition of pL1s is associated with AD. Aim 2 will determine the mechanism of TRIM28 interaction with L1 ORF2p protein and its effect on L1 integration and DSB-formation. This aim will determine whether TRIM28 plays a dual role in the L1 amplification cycle and the mechanism of TRIM28-associated stimulation of L1 retrotransposition. Combined positive outcomes of these aims would justify large-scale studies testing the utility of genomic L1 content in identifying individual risk of developing AD and/or other age-related dementias.

现有R01的目标之一是开发高吞吐量方法，称为 得分，用于检测人DNA中的多态L1（PL1）逆转录子。我们的现有 R01不包括涉及分析阿尔茨海默氏病（AD）专利的任何研究 基因组。但是，这样的分析将在此R01的范围内，因为PL1及其 DNA损伤是资助R01和拟议的行政的共同主题 补充。拟议的研究对AD很重要，因为AD患者的大脑具有 与年龄匹配的对照相比，DNA断裂水平增加，证据支持证明 当斑块和缠结具有时，这种损害会导致AD前临床阶段的神经元丧失 尚未形成。因此，鉴定了基本神经元损失的其他机制 将大大提高我们对AD病因和治疗进展的理解 发展。几种分子机制防止与L1相关的损伤。其中之一 是通过表观遗传沉默的L1启动子对L1表达的TRIM28介导的抑制。 尽管TRIM28在整个大脑的神经元中表达，但L1损伤发生在 海马和大脑皮层，这是AD患者也受到影响的区域。我们的 初步发现表明，与其在L1转录抑制中的作用无关，TRIM28 与L1蛋白相互作用并刺激L1逆转录置。 我们假设AD患者的基因组比正常的基因组更多 受试者，这可能导致与L1相关的增加的神经元损失 DNA损伤，尤其是与Trim28的放松管制结合时。我们将检验我们的假设 通过两个具体的目标。 AIM 1将执行一个案例对照研究，以确定 AD患者（病例）和年龄匹配的受试者的基因组中的PL1s 损伤（控制）。此目标将确定PL1的数量和/或组成是 与AD相关。 AIM 2将确定TRIM28与L1 ORF2P相互作用的机制 蛋白质及其对L1整合和DSB形成的影响。这个目标将决定是否 TRIM28在L1扩增周期和TRIM28相关的机理中起双重作用 刺激L1逆转录。这些目标的结合积极成果将证明是合理的 大规模研究测试了基因组L1含量在识别个人风险中的实用性 发展AD和/或其他与年龄有关的痴呆症。