Interrogating the intersection between diet and ocular autoimmunity

探究饮食与眼部自身免疫之间的交叉点

• 批准号: 10419170
• 负责人: Scott M Plafker
• 金额: $ 58.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419170
• 关键词: Adjuvant; Adoptive Transfer; Adverse effects; Anatomy; Anti-Inflammatory Agents; Autoimmune; Autoimmune Diseases; Autoimmunity; Biological Assay; Blindness; Blood; Brain; Cardiovascular system; Cells; Central Nervous System Diseases; Clinical Trials; Consumption; Demyelinations; Diagnostic; Diet; Diet Habits; Disease; Environment; Erythrocytes; Erythropoietin; Experimental Autoimmune Encephalomyelitis; Eye; Fatty Acids; Fatty acid glycerol esters; Flare; Food; Fumarates; Goals; Health; Homeostasis; ITGAM gene; Immune; Immune Tolerance; Immunohistochemistry; Immunologics; Incidence; Inflammation; Inflammatory; Interleukin-17; Intestinal permeability; Intestines; Leaky Gut; Life Style; Link; Measurement; Mediating; Medium chain triglycerides; Metabolic; Metabolic syndrome; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Natural Immunity; Neuromyelitis Optica; Ocular Pathology; Optic Nerve; Optic Neuritis; Optics; Oral; Outcome; Pain; Pathogenicity; Pathology; Patients; Plasma; Population; Predisposition; Process; Psychophysics; Recombinants; Reducing diet; Reporter; Resolution; Retina; Site; Sjogren' s Syndrome; Source; Spinal Cord; T-Lymphocyte; Testing; Time; Treatment Efficacy; Uveitis; Vision; Work; adaptive immunity; autoreactive T cell; base; cytokine; design; diagnostic biomarker; dietary; dysbiosis; empowered; experience; gut health; gut homeostasis; gut microbiome; immunoregulation; improved; in vivo; inflammatory marker; inflammatory milieu; ketogenic diet; lipidomics; migration; monocyte; motor deficit; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nerve damage; neuroprotection; novel; nutritional approach; oculomotor; premature; preservation; prevent; reconstitution; remyelination; repaired; standard of care; systemic inflammatory response; treatment response; visual motor

5-8% of the US population suffers from at least one autoimmune disease. An upward trajectory has occurred in the last few decades, implicating diet, lifestyle, environment, and improved diagnostics. The contributions of diet to this increased incidence have been attributed to the excessive consumption of ultra- processed foods that drive systemic inflammation. Just as poor dietary habits can compromise health, diseases can potentially be treated or prevented by diets that promote and restore metabolic homeostasis. Consistent with this notion, we have demonstrated that a well-formulated ketogenic diet (KD), containing medium chain triglycerides as the primary source of fat, can mitigate the visual and motor deficits in a mouse model of autoimmunity called MOG-EAE. This model reconstitutes many of the signature ocular and motor pathologies experienced by patients with Multiple Sclerosis (MS) and Neuromyelitis Optica. The goals of this application are: (1) to identify the immuno-modulatory mechanisms by which a well-formulated KD preserves metabolic homeostasis, gut health, and immune tolerance, (2) to determine if a KD can serve as an adjuvant to enhance the vision-sparing capacity of existing MS treatments and (3) to determine if the KD can repair damaged nerves by promoting remyelination. Our leading hypothesis is that a well-formulated KD promotes immune tolerance and neuroprotection by creating a systemic anti-inflammatory milieu. Specific Aim 1 will identify the mechanisms linking gut integrity and plasma fatty acids to optic neuritis, a painful and often blinding inflammation of the optic nerve experienced by MS patients. Specific Aim 2 will determine if the KD can enhance the vision-sparing capacity of several current MS treatments. Specific Aim 3 will identify novel immunological mechanisms that mediate the efficacy of the KD during autoimmune challenge. This work combines psychophysical measurements of vision, a novel reporter mouse, gut permeability assays, high resolution lipidomics, adoptive transfer assays, and blood analyses for markers of inflammation and metabolic/cardiovascular status. This work is distinguished from previous studies by comparing the anatomic-specific effects of the KD at each of the primary sites of MS lesions (optic nerve, spinal cord, and brain). These studies are designed to overcome the serious adverse effects associated with current MS treatments by empowering patients with a readily-implementable dietary strategy to prevent or reduce flare ups of optic neuritis and other debilitating sequelae. Additionally, these findings will provide a framework to facilitate interpreting outcomes from the numerous clinical trials currently testing the KD across a range of diseases.

5-8%的美国人患有至少一种自身免疫性疾病。一个上升的轨迹 发生在过去几十年中，涉及饮食，生活方式，环境和改进的诊断。的 饮食对这种发病率增加的贡献归因于过量食用超 导致全身炎症的加工食品就像不良的饮食习惯会危害健康一样， 可以通过促进和恢复代谢稳态的饮食来治疗或预防。一致 根据这一概念，我们已经证明，含有中链的配方良好的生酮饮食（KD） 甘油三酯作为脂肪的主要来源，可以减轻小鼠模型的视觉和运动缺陷 称为MOG-EAE的自身免疫。该模型重建了许多标志性的眼部和运动病理 多发性硬化症（MS）和视神经肌萎缩症患者所经历的。此应用程序的目标 （1）确定一种良好配制的KD通过其保持代谢平衡的免疫调节机制， 稳态，肠道健康和免疫耐受，（2）以确定KD是否可以作为佐剂来增强免疫耐受性。 现有MS治疗的视力保留能力和（3）确定KD是否可以修复受损的神经 通过促进髓鞘再生我们的主要假设是，一个良好的制定KD促进免疫耐受 和神经保护作用。具体目标1将确定机制 将肠道完整性和血浆脂肪酸与视神经炎联系起来，视神经炎是一种疼痛且经常致盲的视神经炎症 MS患者经历的神经。具体目标2将确定KD是否可以增强视觉保护 目前的几种MS治疗方法。具体目标3将确定新的免疫机制， 介导自身免疫激发期间KD的功效。这项工作结合了心理和物理 视觉测量，新型报告小鼠，肠道通透性测定，高分辨率脂质组学，过继 转移测定和炎症标志物和代谢/心血管状态的血液分析。这项工作 通过比较KD在每个原发灶的解剖学特异性效应， MS病变部位（视神经、脊髓和脑）。 这些研究旨在克服与当前MS相关的严重不良反应 通过赋予患者易于实施的饮食策略来预防或减少发作， 视神经炎和其他使人衰弱的后遗症。此外，这些发现将提供一个框架， 解释目前在一系列疾病中测试KD的众多临床试验的结果。