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

基本信息

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
项目类别：
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&apos 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

项目摘要

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。向上的轨迹有发生在过去几十年里，涉及饮食、生活方式、环境和诊断方法的改进。这饮食导致发病率增加的原因是过度摄入超加工食品会导致全身炎症。正如不良的饮食习惯会损害健康一样，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，我们已经证明了精心配制的生酮饮食（KD），含有中链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学多发性硬化症（MS）和视神经脊髓炎患者经历过。此应用程序的目标是：（1）确定免疫调节机制，精心配制的生酮饮食可以保护代谢体内平衡、肠道健康和免疫耐受性，(2) 以确定 KD 是否可以作为增强免疫的佐剂现有多发性硬化症治疗的视力保护能力，以及 (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，精心配制的生酮饮食可以促进免疫耐受通过创造全身抗炎环境来保护神经。具体目标 1 将确定机制肠道完整性和血浆脂肪酸与视神经炎有关，视神经炎是一种痛苦且常常致盲的视神经炎症 MS 患者所经历的神经。具体目标 2 将确定 KD 是否可以增强视力保护目前几种 MS 治疗的能力。具体目标 3 将确定新的免疫机制在自身免疫挑战期间介导 KD 的功效。这部作品结合了心理物理学视力测量、新型报告小鼠、肠道通透性测定、高分辨率脂质组学、过继转移测定以及炎症标记物和代谢/心血管状态的血液分析。这部作品通过比较 KD 在每个主要部位的解剖特异性效应，与之前的研究区分开来。 MS 病变部位（视神经、脊髓和大脑）。这些研究旨在克服与当前多发性硬化症相关的严重不利影响通过为患者提供易于实施的饮食策略来预防或减少发作来进行治疗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，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。