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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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/文摘