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%的美国人口至少患有一种自身免疫性疾病。一个向上的轨迹已经 发生在过去几十年，与饮食、生活方式、环境和改进的诊断有关。这个 饮食对发病率增加的贡献被归因于过度摄入超 会引发全身炎症的加工食品。正如不良的饮食习惯会损害健康、疾病一样 可以通过促进和恢复代谢动态平衡的饮食来治疗或预防。一致 在这个概念下，我们已经证明了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，可以缓解小鼠的视觉和运动障碍 自身免疫性疾病称为MOG-EAE。这个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)和视神经脊髓炎患者经历的。此应用程序的目标是 是：(1)确定免疫调节机制，通过这些机制，良好配方的KD保存代谢 动态平衡、肠道健康和免疫耐受，(2)确定KD是否可以作为佐剂来增强 现有多发性硬化症治疗的视觉保护能力；(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，配方良好的KD可促进免疫耐受 以及通过创造全身性抗炎环境来保护神经。具体目标1将确定这些机制 肠道完整性和血浆脂肪酸与视神经炎有关，视神经炎是一种疼痛且经常致盲的视神经炎症 多发性硬化症患者的神经体验。具体目标2将决定KD是否能增强视力保护 目前几种多发性硬化症治疗的能力。具体目标3将确定新的免疫机制， 在自身免疫攻击过程中调节KD的疗效。这项工作结合了心理物理学 视力测量，新型报告小鼠，肠道通透性分析，高分辨率脂质组学，采用 转移分析，以及血液分析炎症和代谢/心血管状态的标志物。这部作品 与以前的研究不同的是，通过比较KD在每个初级 多发性硬化病变的部位(视神经、脊髓和脑)。 这些研究旨在克服与当前多发性硬化症相关的严重不良影响 通过为患者提供易于实施的饮食策略来预防或减少突发事件的治疗 视神经炎和其他令人衰弱的后遗症。此外，这些发现将提供一个框架，以促进 解释目前在一系列疾病中测试KD的众多临床试验的结果。