Human Endogenous retroviruses as potential early markers for Alzheimer's disease

项目摘要 阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征在于进行性损害和神经元丢失。 中枢神经系统中的神经元。目前阿尔茨海默病的诊断主要依赖于记录 智力下降，此时阿尔茨海默氏症已经造成严重的脑损伤。迫切需要 寻找新的方法，在这些毁灭性的症状开始之前检测阿尔茨海默氏症。识别待定认知 在早期阶段的损害可以帮助设计干预措施，可能会降低认知能力下降的风险。人类 内源性逆转录病毒（ERV）已经整合到哺乳动物基因组中数百万年，并且包括 高达5-8%的人类基因组，相比之下，1-2%的蛋白质编码序列。相比 许多研究描述了蛋白质及其功能，但很少有研究对蛋白质的影响。 人类ERV对健康和疾病的影响了解每个ERV如何调节自身及其相关的 基因组元件-功能蛋白质，疾病相关抗原或基因组调节因子-在 确定ERV对人类健康和疾病的影响。据报告，ERV 在AD患者的大脑中转录活跃。此外，ERV激活也与认知功能有关。 小鼠的损伤。在父母补助金中，NIH/NCI R 01 CA 226570“非洲人侵袭性前列腺癌” 美国人与间质中免疫调节基因的调节相关”，我们提出， 在前列腺肿瘤微环境中通过ERV控制抗病毒免疫应答途径可能有助于 不同种族患者前列腺癌进展的差异。ERV高度重复 并且在整个基因组中存在多个拷贝，使得难以使用现有的计算方法来研究它们。 工具.大多数研究使用PCR，可以检测到一些ERV。我们开发了一种计算工具来研究 基因组水平的ERV，允许在全球水平检测ERV变化。应用本小说 通过计算方法，我们已经能够将临床结果与前列腺中ERVs的表达相关联， 宫颈癌在这里，我们建议将这些研究扩展到AD，并假设ERV激活的变化 有助于AD的炎症和病理生理学。我们将从两个方面来检验我们的假设。一是 将研究AD患者外周血单个核细胞（PBMC）中ERV表达的总体变化 和轻度认知障碍（MCI）患者以及健康个体（年龄匹配）。二是 确定来自所有三个组群（年龄匹配）的海马组织中ERV表达的总体变化。 ERV变化的鉴定不仅可以为旨在减毒的策略提供新的分子靶标， 逆转录病毒元件传感治疗痴呆症和神经精神疾病，但也可能作为潜在的早期 AD的生物标志物。

PROJECT SUMMARY Alzheimer’s disease (AD) is a neurodegenerative disorder that is marked by progressive damage and loss of neurons in the central nervous system. Current diagnosis of Alzheimer's disease relies largely on documenting mental decline, at which point Alzheimer's has already caused severe brain damage. There is an urgent need for novel methods to detect Alzheimer's before these devastating symptoms begin. Identifying pending cognitive impairment at an early stage can help design interventions that may reduce the risk of cognitive decline. Human Endogenous Retroviruses (ERVs) have integrated into mammalian genome over millions of years and comprise up to 5–8% of the human genome, as compared to 1-2% of protein coding sequences. Compared to the numerous studies describing proteins and their functions, very few studies have been performed on the impact of human ERVs on health and disease. Understanding how each ERV modulates both itself and its related genomic elements – functional proteins, disease-associated antigens, or genomic regulators – is crucial in determining the impact that ERVs can have on human health and diseases. ERVs have been reported to be transcriptionally active in the brains of AD patients. In addition, ERV activation is also associated with cognitive impairment in mice. In the parent grant, NIH/NCI R01CA226570 “Aggressive prostate cancer of African Americans is correlated with regulation of immunoregulatory genes in stroma”, we proposed that an epigenetic control of the antiviral immune response pathways via ERVs in prostate tumor microenvironment may contribute to differences in prostate cancer progression among patients of different racial groups. ERVs are highly repetitive and present in multiple copies throughout genome making it difficult to study them using existing computational tools. Most studies use PCR that can detect a few ERVs. We have developed a computational tool to study ERVs at the genome level, allowing detection of ERV changes at the global level. Applying this novel computational method, we have been able to correlate clinical outcomes with ERVs expression in prostate and cervical cancer. Here, we propose to extend these studies to AD and hypothesize that changes in ERV activation contribute to the inflammation and pathophysiology in AD. We will examine our hypothesis in two aims. First, we will investigate the global changes in ERV expression in peripheral blood mononuclear cells (PBMCs) from AD and mild cognitive impairment (MCI) patients, as well as healthy individuals (age matched). Second, we will determine the global changes in ERV expression in hippocampus tissue from all three cohorts (age matched). Identification of ERV changes may not only provide novel molecular target for strategies aimed at attenuating retroviral element sensing to treat dementia and neuropsychiatric disorders, but may also serve as potential early biomarkers for AD.