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.

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