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: 10597231
• 负责人: Scott M Plafker
• 金额: $ 56.21万
• 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/10597231
• 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; IL17 gene; ITGAM gene; Immune; Immune Tolerance; Immunohistochemistry; Immunologics; Incidence; Inflammation; Inflammatory; Intestinal permeability; Intestines; Leaky Gut; Life Style; Link; Measurement; Mediating; Medium chain triglycerides; Metabolic; Metabolic syndrome; Modeling; Motor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Natural Immunity; Neuromyelitis Optica; Ocular Pathology; Optic Nerve; Optic Neuritis; Optics; Oral Administration; Outcome; Pain; Pathogenicity; Pathology; Patients; Plasma; Population; Predisposition; Process; Proliferating; Psychophysics; Recombinant Erythropoietin; Reducing diet; Reporter; Resolution; Retina; Site; Sjogren' s Syndrome; Source; Spinal Cord; T-Lymphocyte; Testing; Time; Treatment Efficacy; Uveitis; Vision; Visual; Work; adaptive immunity; autoreactive T cell; cytokine; design; diagnostic biomarker; dietary; dysbiosis; empowerment; 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; premature; preservation; prevent; reconstitution; remyelination; repaired; standard of care; systemic inflammatory response; treatment response

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％的美国人口患有至少一种自身免疫性疾病。向上的轨迹有 发生在过去几十年中，涉及饮食，生活方式，环境和改善的诊断。这 饮食对这种增加的发病率的贡献已归因于超级消费过多 加工的食物会导致全身炎症。就像饮食习惯差会损害健康一样，疾病 可以通过促进和恢复代谢稳态的饮食来治疗或预防。持续的 有了这个概念，我们已经证明了包含中链的良好成熟的生酮饮食（KD） 甘油三酸酯是脂肪的主要来源，可以减轻鼠标模型中的视觉和运动缺陷 自身免疫称为Mog-eee。该模型重构许多签名的眼和运动病理 多发性硬化症患者（MS）和神经霉素炎的患者经历。该应用程序的目标 为：（1）确定良好成熟KD代谢的免疫调节机制 稳态，肠道健康和免疫耐受性，（2）确定KD是否可以作为辅助者来增强 现有MS处理的视力能力和（3）确定KD是否可以修复受损的神经 通过促进再生。我们的主要假设是，良好的KD促进了免疫耐受性 和神经保护通过创建系统性抗炎环境。特定目标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，视神经炎是痛苦且经常令人眼花blim乱的炎症 MS患者经历的神经。特定的目标2将确定KD是否可以增强视力的比较 当前几种MS治疗的能力。特定目标3将确定新型免疫机制 在自身免疫性挑战期间调解KD的功效。这项工作结合了心理物理 视力的测量，一种新颖的记者鼠标，肠渗透性测定，高分辨率脂肪组学，收养 转移测定法，以及炎症和代谢/心血管状态标记的血液分析。这项工作 通过比较KD在每个主要的研究中的解剖学特异性效应来区分与以前的研究。 MS病变的部位（视神经，脊髓和大脑）。 这些研究旨在克服与当前MS相关的严重不利影响 通过赋予患者的能力，采用易于实现的饮食策略来预防或减少爆发的治疗 视神经炎和其他衰弱的后遗症。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。