ABCA1 regulates white matter remodeling and oligodendrogenesis after stroke

ABCA1 调节中风后白质重塑和少突胶质细胞生成

• 批准号: 8944748
• 负责人: Xu Cui
• 金额: $ 32.48万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8944748
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Adult; Affect; Agonist; Apolipoprotein E; Astrocytes; Attenuated; Axon; Blood; Brain; Brain Hypoxia-Ischemia; Cell Culture Techniques; Cell Proliferation; Cerebrospinal Fluid; Cholesterol; Clinical; Clinical Trials; Coculture Techniques; Conditioned Culture Media; Data; Demyelinations; Dendrites; Development; Distal; Environment; Exhibits; Gene Expression; Genes; Glean; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hypoxia; Impairment; In Situ; In Vitro; Injury; Ischemia; Liver; Measures; Mediating; Metabolism; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mus; Mutation; Myelin; Nervous System Physiology; Neuraxis; Neurites; Neurologic; Neurological outcome; Neurons; Oligodendroglia; Outcome; Pathway interactions; Patients; Peripheral Nervous System Diseases; Plasma; Play; Recovery of Function; Regulation; Rodent; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Stroke; Synapses; System; Tangier Disease; Testing; Transportation; Wild Type Mouse; axon growth; axon regeneration; axonal degeneration; brain research; cholesterol transporters; cognitive recovery; disability; functional outcomes; high density lipoprotein-1; high density lipoprotein-apolipoprotein E; improved; in vivo; insight; lipoprotein cholesterol; macrophage; mortality; myelination; neuron loss; novel; particle; post stroke; public health relevance; receptor; remyelination; restoration; stroke recovery; stroke therapy; synaptogenesis; tool; virtual; white matter; white matter change; white matter damage

 DESCRIPTION (provided by applicant): Stroke is a major cause of white matter (WM) damage which induces long-term disability. There is limited WM- remodeling in the adult brain. Many neuroprotective treatments of stroke have failed in clinical trials because they cannot protect WM. Therefore, there is a compelling need to investigate the mechanism underlying WM- remodeling and oligodendrogenesis of the adult brain and to develop effective long-term stroke therapy. Cellular cholesterol modulates axonal and dendritic outgrowth and is required for myelination. The level of HDL-cholesterol is related to the progression and recovery of stroke patients. ATP-binding cassette transporter A 1 (ABCA1) is a major cholesterol transporter and plays critical roles in regulation of HDL-cholesterol and ApoE synthesis and metabolism in the central nervous system. Brain specific-ABCA1 deficient (ABCA1-B/-B) mice have very low brain HDL-cholesterol/ApoE level, and exhibit neuronal ultrastructure changes and functional deficits. Both HDL-cholesterol and ApoE increase neurite outgrowth in culture conditions. Our preliminary study shows that ABCA1-B/-B mice exhibited increased WM damage and reduced oligodendrogenesis and exacerbated neurological functional deficits after stroke. Primary cultured neurons derived from ABCA1-B/-B mice show decreased neurite outgrowth, which can be attenuated by HDL treatment. ABCA1-B/-B astrocyte-conditioned media also decreased wild type neurite outgrowth after hypoxic ischemia. Therefore, we propose the following three specific aims: Aim1 To investigate whether brain-deficient in ABCA1 exhibits decreases in WM-remodeling and axonal growth after stroke. ABCA1 -B/-B and floxed-control mice will be subjected to stroke, WM-changes and oligodendrogenesis will be measured. Aim2 To investigate molecular mechanism underlying ABCA1 in regulation of WM-remodeling and oligodendrogenesis after stroke, we will examine whether ABCA1 regulates brain HDL and ApoE level, and whether brain HDL and ApoE levels mediate ABCA1-induced WM-remodeling and oligodendrogenesis after stroke. Aim3 To investigate cellular mechanisms of ABCA1 in regulation of WM-remodeling and oligodendrogenesis, we will examine neurons and oligodendrocytes and the cross talk of astrocytes with neurons and oligodendrocytes on ABCA1-induced WM- remodeling and oligodendrogenesis in vitro and in vivo. We expect that ABCA1 deficient brain will exhibit significant decreases in HDL and ApoE level, and decreases WM-remodeling and oligodendrogenesis as well as reduced functional outcome after stroke. The level of HDL/ApoE in brain or cerebrospinal fluid will, at least partially, mediate ABCA1-induced WM-remodeling and oligodendrogenesis in the ischemic brain after stroke. To our knowledge, no one has investigated the functional effect of ABCA1 on oligodendrogenesis and WM- remodeling post-stroke recovery, especially by using ABCA1-B/-B mice. The new insights gleaned from this study will contribute to our understanding of the beneficial role of ABCA1/HDL-C/ApoE in brain plasticity which will impact development of rational restorative approaches to improve neurological outcome for stroke patients.

 描述（由申请人提供）：中风是导致长期残疾的白质（WM）损伤的主要原因。许多中风的神经保护治疗在临床试验中都失败了。因此，迫切需要研究成人大脑 WM 重塑和少突胶质细胞生成的机制，并开发有效的长期中风疗法。 HDL 胆固醇水平与中风患者的进展和恢复有关，ATP 结合盒转运蛋白 A 1 (ABCA1) 是一种主要的胆固醇转运蛋白，在 HDL 胆固醇和 ApoE 的调节中发挥着关键作用。中枢神经系统中的合成和代谢 脑特异性 ABCA1 缺陷 (ABCA1-B/-B) 小鼠的脑 HDL-胆固醇/ApoE 水平非常低，并且表现出我们的初步研究表明，ABCA1-B/-B 小鼠在中风后表现出 WM 损伤增加、少突胶质细胞生成减少以及神经功能缺陷加剧。来自 ABCA1-B/-B 小鼠的神经突生长减少，HDL 处理也可以减弱这种现象。因此，我们提出以下三个具体目标： 目的1 研究ABCA1 缺陷的小鼠在中风后是否表现出WM 重塑和轴突生长减少。将遭受中风，将测量 WM 变化和少突胶质细胞生成。目的2 研究 ABCA1 调节 WM 重塑和少突胶质细胞形成的分子机制。中风后少突胶质细胞生成，我们将检查ABCA1是否调节脑HDL和ApoE水平，以及脑HDL和ApoE水平是否介导中风后ABCA1诱导的WM重塑和少突胶质细胞生成Aim3目的研究ABCA1调节WM重塑和少突胶质细胞发生的细胞机制。 ，我们将检查ABCA1诱导的WM-神经元和少突胶质细胞以及星形胶质细胞与神经元和少突胶质细胞的串扰我们预计，ABCA1 缺陷的大脑将表现出 HDL 和 ApoE 水平显着降低，并降低 WM 重塑和少突胶质细胞生成以及中风后脑内 HDL/ApoE 水平的降低。脑脊液至少会部分介导中风后缺血性大脑中 ABCA1 诱导的 WM 重塑和少突胶质细胞生成。研究了 ABCA1 对少突胶质细胞生成和中风后 WM 重塑的功能影响，特别是使用 ABCA1-B/-B 小鼠。从这项研究中收集到的新见解将有助于我们了解 ABCA1/HDL-C 的有益作用。 /ApoE 在大脑可塑性中的作用，这将影响合理的恢复方法的发展，以改善中风患者的神经系统结果。