Epigenetic regulation of oligodendrocyte regeneration in subcortical ischemic vascular dementia

皮质下缺血性血管性痴呆少突胶质细胞再生的表观遗传调控

• 批准号: 10509535
• 负责人: Ken Arai
• 金额: $ 46.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509535
• 关键词: Affect; Aging; Alzheimer' s Disease; Axon; Biological Process; Brain; Brain Infarction; Cell Culture System; Cell Differentiation process; Cell Proliferation; Cell physiology; Cerebrovascular Disorders; Cerebrum; Chronic; Chronic Phase; Clinical; Corpus Callosum; DNA; DNA Maintenance; DNA Methylation; DNA Modification Methylases; DNMT3a; Data; Disease; Enzymes; Epigenetic Process; Equilibrium; Exhibits; Female; Fiber; Functional disorder; Gene Expression; Generations; Histone Deacetylase; Histones; Hypoxia; Impaired cognition; In Vitro; Knowledge; Mediating; Molecular; Mus; Myelin Sheath; Natural regeneration; Neuraxis; Neurodegenerative Disorders; Oligodendroglia; Organ; Pathologic; Patients; Pattern; Play; Population; Proliferating; Rattus; Recovery; Role; Sex Differences; Small Interfering RNA; Syndrome; System; Testing; Therapeutic; Vascular Dementia; White Matter Disease; aging population; behavior test; cerebral hypoperfusion; cerebrovascular pathology; chromatin modification; cognitive function; epigenetic regulation; experimental study; histone acetyltransferase; histone modification; in vivo; insight; loss of function; male; mouse model; neurogenesis; novel; object recognition; oligodendrocyte precursor; precursor cell; pup; repaired; response; transcriptome sequencing; transcriptomics; vascular cognitive impairment and dementia; white matter; white matter damage

PROJECT SUMMARY/ABSTRACT Epigenetic regulation is an important biological process that regulates gene expression. Past studies have demonstrated that epigenetic regulation (e.g. histone modification and DNA methylation) is closely related to cell differentiation in most organs, including neurogenesis in the brain. In addition, dysregulation of epigenetic regulation is related to some chronic neurodegenerative diseases, such as Alzheimer’s disease. However, little is known how the epigenetic system contributes to the pathology of cerebrovascular diseases, including vascular cognitive impairment and dementia (VCID). Subcortical ischemic vascular dementia (SIVD) is the most common subtype of VCID syndrome that occurs with aging. SIVD is clinically defined as cognitive decline with evidence of subcortical brain infarction. Patients with SIVD suffer from white matter degeneration, many of whom exhibit prolonged cerebral hypoperfusion. Although the number of patients with SIVD is predicted to increase with the aging population, to date there is no established treatment for this pathological condition. Since white matter dysfunction is a major feature of this disease, it is important to elucidate the cellular and molecular mechanisms of white matter damage and recovery after cerebral hypoperfusion. Because oligodendrocytes do not proliferate, oligodendrocyte precursor cells (OPCs) play an indispensable role in regulating oligodendrocyte numbers. Regulatory mechanisms regarding OPC proliferation and differentiation have been extensively examined, and histone modification is confirmed to contribute to the generation of oligodendrocytes from OPCs. However, little is known whether and how DNA methylation by DNA methyltransferase enzymes (DNMTs) is involved in oligodendrocyte generation, especially under the conditions of white matter diseases. This is the major gap in knowledge that we seek to fill. This exploratory study aims to reveal the roles of DNMTs in oligodendrogenesis (oligodendrocyte regeneration) in cerebral white matter, by testing three hypotheses: (i) DNMTs regulate OPC proliferation and differentiation, (ii) expression level of DNMTs would change after cerebral hypoperfusion as a compensatory response, and (iii) downregulating DNMTs would decrease oligodendrogenesis after cerebral hypoperfusion in mice. For this purpose, we propose two integrated aims as below. In Aim 1, we will examine the roles of DNMTs in OPC proliferation and differentiation using in vitro cell culture system. In Aim 2, we aim to show that OPC proliferation and differentiation after cerebral hypoperfusion is dampened in OPC-DNMT1 or OPC-DNMT3a deficient mice. This exploratory study will provide novel insights into the mechanisms by which the epigenetic regulator DNMTs contribute to compensatory oligodendrogenesis during cerebral hypoperfusion.

项目摘要/摘要 表观遗传调节是调节基因表达的重要生物学过程。过去的研究有 证明表观遗传调节（例如Hisstone修饰和DNA甲基化）与 大多数器官的细胞分化，包括大脑中的神经发生。另外，失调 表观遗传调节与某些慢性神经退行性疾病有关，例如阿尔茨海默氏病。 然而，几乎不知道表观遗传系统如何促进脑血管的病理 疾病，包括血管认知障碍和痴呆（VCID）。 皮层缺血性血管痴呆（SIVD）是发生的最常见的VCID综合征亚型 随着衰老。 SIVD在临床上定义为认知能力下降，并具有皮层下脑梗塞的证据。 SIVD患者患有白质变性，其中许多人暴露了长时间的大脑 灌注不良。尽管预计患有SIVD的患者数量会随着衰老而增加 迄今为止，人口尚无针对这种病理状况的既定治疗方法。由于白质 功能障碍是该疾病的主要特征，重要的是阐明细胞和分子 白质损伤和脑灌注后恢复的机制。 由于少突胶质细胞不会增殖，因此少突胶质细胞前体细胞（OPC）的作用是必不可少的 在控制少突胶质数中的作用。 OPC增殖和 已经对差异化进行了广泛的检查，并确认了Hisstone的修改有助于 OPC的少突胶质细胞产生。但是，几乎不知道是否以及如何通过 DNA甲基转移酶（DNMT）参与少突胶质细胞的产生，特别是在 白质疾病的疾病。这是我们寻求填补的知识的主要差距。 这项探索性研究旨在揭示DNMT在寡胶质发生中的作用（少突胶质细胞 在脑白质中的再生），通过检验三个假设：（i）DNMTS调节OPC增殖 和分化，（ii）DNMT的表达水平将在脑灌注不足之后变化 补偿性反应，（iii）下调DNMT将减少脑发生少突义因素。 小鼠灌注不足。为此，我们提出了下面的两个综合目标。在AIM 1中，我们将 使用体外细胞培养系统检查DNMT在OPC增殖和分化中的作用。目标 2，我们的目的是表明OPC的增殖和分化在脑部灌注后被抑制 OPC-DNMT1或OPC-DNMT3A缺陷小鼠。这项探索性研究将为您提供新的见解 表观遗传调节剂DNMT有助于代偿性寡聚的机制 在脑灌注不足期间。