Targeting Cholesterol Homeostasis to maintain vision in MS-like optic neuritis

针对多发性硬化症样视神经炎的胆固醇稳态以维持视力

• 批准号: 10657163
• 负责人: Oliver W Gramlich
• 金额: $ 31.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657163
• 关键词: 3-Dimensional; ATP binding cassette transporter 1; Acids; Acute; Affect; Agonist; Animal Experimentation; Animal Model; Animals; Aspirin; Autoimmune; Autopsy; Axon; Biological Assay; Blindness; Brain; Carrier Proteins; Cell Line; Cell Survival; Cells; Central Nervous System; Cholesterol; Cholesterol Homeostasis; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Disease Progression; Dyes; Electroretinography; Event; Experimental Autoimmune Encephalomyelitis; Exposure to; Eye; Feedback; Future; Goals; Harvest; Healthcare Systems; Human; Immunohistochemistry; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Interferon Type II; Investigation; Lysophosphatidylcholines; Mediating; Modeling; Molecular; Molecular Biology; Multiple Sclerosis; Mus; Myelin; Nerve Tissue; Neurons; Oligodendroglia; Ophthalmology; Optic Nerve; Optic Neuritis; Optical Coherence Tomography; Organoids; Outcome; Outcome Measure; Pathology; Pathway interactions; Patients; Pattern; Prevalence; Process; Recovery; Recovery of Function; Recycling; Reporter; Resources; Retina; Retinal Ganglion Cells; Role; Sterols; Synaptic plasticity; System; Systems Biology; TNF gene; Testing; Therapeutic; Therapeutic Studies; Time; Tissues; Vision; Visual evoked cortical potential; Visual impairment; cell type; central nervous system demyelinating disorder; experience; experimental study; functional disability; improved; in vivo; in vivo Model; induced pluripotent stem cell; inhibitor; innovation; insight; mevalonate; multiple sclerosis patient; myelination; neuronal survival; neuroprotection; novel therapeutics; preservation; prevent; regenerative; remyelination; repaired; response; restoration; retinal ganglion cell degeneration; retinogeniculate; reverse cholesterol transport; single-cell RNA sequencing; social; success; synaptogenesis; targeted treatment; transcriptome sequencing; translational study; uptake

Project Summary/Abstract: Acute optic neuritis (ON) is often the initial presenting manifestation of autoimmune demyelinating disorders such as Multiple Sclerosis (MS). Good recovery of vision after ON is common, but a considerable number of MS patients experience poor outcomes with severe visual impairment and permanent blindness as disease progresses. The increasing prevalence of MS will cause an immense social and financial challenge for health care systems and more studies are needed to improve treatment success in these diseases. Impaired recycling of cholesterol-rich myelin debris and decreased de novo synthesis of cholesterol have been identified as key limiting factors of recovery in demyelinating animal models. We have demonstrated decreased expression of the main cholesterol efflux transporter1, Abca1, and altered cholesterol homeostasis in the retinogeniculate system of animals with Experimental Autoimmune Encephalomyelitis (EAE)-ON. However, the exact mechanism by which changes in Abca1 expression affect cholesterol recycling remain elusive. We hypothesize that this impairment in cholesterol synthesis and transport significantly affects RGC survival, integrity of synaptic plasticity and remyelination and that restoration of cholesterol homeostasis via Abca1 regulatory feedback ameliorates visual impairment. In specific aim 1, we will determine the regulatory influence of ABCA1 expression on sterol synthesis and synaptic plasticity, cholesterol transport, and myelination in vitro. Eye and brain organoids from healthy subjects and MS patients will be exposed to Abca1 inhibitors, TNFα/IFNγ, or the demyelinating agent Lysolecithin. Effects of rescued Abca1 expression on sterol synthesis, cholesterol uptake and transport, synaptogenesis and myelination will be examined using single-cell RNA-sequencing, immunohistochemistry, and cholesterol efflux assays. In specific aim 2, we will determine the molecular, functional, and structural impact of Abca1 expression changes in the retinogeniculate pathway of EAE-ON and MS. EAE-ON will be induced in mice and effects of Abca1 expression changes will be determined using optokinetic response, optical coherence tomography, pattern electroretinography, and visual evoked potentials, followed by postmortem molecular and histopathologic analysis. Also, disruption in cholesterol homeostasis will be determined in MS donor eye tissue. Our proposed experiments will significantly advance the understanding of the role of cholesterol homeostasis in MS-like ON and provide an invaluable resource for future translational and therapeutic studies.

项目摘要/摘要： 急性视神经神经（ON）通常是自身免疫的初始表现表现 脱髓鞘性疾病，例如多发性硬化症（MS）。良好的视力恢复是常见的， 但是，大量的MS患者在严重的视力障碍时经历较差的结果 随着疾病的发展，永久失明。 MS的患病率的增加将导致 对医疗保健系统的IMSENSE社会和财务挑战需要更多的研究 改善这些疾病的治疗成功。 富含胆固醇富含胆固醇的髓磷脂的回收受损，并改善了从头合成 胆固醇已被确定为脱髓鞘模型中恢复的关键限制因素。我们 已经证明主胆固醇外排Trans蛋白1，ABCA1和 通过实验性的动物视网膜生成系统中的胆固醇稳态改变了胆固醇的稳态 自身免疫性脑脊髓炎（EAE）-ON。但是，ABCA1变化的确切机制 表达会影响胆固醇回收仍然难以捉摸。我们假设这种障碍 胆固醇合成和转运显着影响RGC的存活，突触可塑性的完整性和 通过ABCA1调节反馈来恢复胆固醇稳态的恢复 改善视觉障碍。 在特定目标1中，我们将确定ABCA1表达对固醇的调节作用 体外合成和突触可塑性，胆固醇的转运和髓鞘化。眼睛和大脑 来自健康受试者和MS患者的类器官将暴露于ABCA1抑制剂，TNFα/IFNγ或 脱髓鞘剂溶血石。拯救ABCA1表达对固醇合成的影响， 将使用单细胞检查胆固醇的吸收和运输，突触发生和髓鞘形成 RNA测序，免疫组织化学和胆固醇外排测定。在特定的目标2中，我们将 确定ABCA1表达变化的分子，功能和结构影响 EAE-ON和MS的视网膜生成途径。 EAE-ON将在小鼠和ABCA1的影响中诱导 表达变化将使用光动力响应，光学相干断层扫描， 图案电图和视觉诱发电位，然后是尸体后分子和 组织病理学分析。此外，胆固醇稳态的破坏将在女士的供体中确定 眼组织。 我们提出的实验将大大提高人们对胆固醇作用的理解 类似于MS的体内平衡，并为未来的翻译和治疗提供了宝贵的资源 研究。