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.

项目总结/摘要 表观遗传调控是调控基因表达的重要生物学过程。过去的研究 表明表观遗传调控（如组蛋白修饰和DNA甲基化）与 大多数器官中的细胞分化，包括大脑中的神经发生。此外， 表观遗传调控与一些慢性神经退行性疾病有关，如阿尔茨海默病。 然而，表观遗传系统如何在脑血管病的病理中起作用还知之甚少 血管性认知障碍和痴呆（VCID）。 皮质下缺血性血管性痴呆（SIVD）是VCID综合征中最常见的亚型， 随着年龄的增长。SIVD在临床上被定义为认知能力下降，伴有皮质下脑梗死的证据。 SIVD患者患有白色变性，其中许多人表现出长时间的脑梗死。 低灌注尽管预计SIVD患者的数量会随着年龄的增长而增加， 人口中，迄今为止，这种病理状况还没有既定的治疗方法。因为白色物质 功能障碍是这种疾病的主要特征，重要的是要阐明细胞和分子 脑低灌注后白色物质损伤及恢复机制的研究 由于少突胶质细胞不增殖，少突胶质细胞前体细胞（OPCs）发挥着不可或缺的作用。 在调节少突胶质细胞数量中的作用。关于OPC增殖的调控机制， 分化已被广泛研究，组蛋白修饰被证实有助于 从OPC产生少突胶质细胞。然而，很少有人知道DNA甲基化是否以及如何通过 DNA甲基转移酶（DNMT）参与少突胶质细胞的生成，特别是在 白色物质疾病的情况。这是我们试图填补的知识空白。 本研究旨在揭示DNMTs在少突胶质细胞发生中的作用 再生）在大脑白色物质，通过测试三个假设：（i）DNMT调节OPC增殖 （ii）脑低灌注后DNMT表达水平发生变化， （iii）下调DNMT会减少脑缺血后少突胶质细胞的发生。 低灌注小鼠。为此，我们提出以下两个综合目标。在目标1中，我们 使用体外细胞培养系统检测DNMT在OPC增殖和分化中的作用。在Aim中 2，我们的目的是表明脑灌注不足后OPC的增殖和分化受到抑制， OPC-DNMT 1或OPC-DNMT 3a缺陷型小鼠。这项探索性的研究将提供新的见解， 表观遗传调节因子DNMT促进补偿性少突胶质细胞发生的机制 脑灌注不足的时候