Understanding the role of aromatic amino acid derived metabolic toxins in neuroinflammation

了解芳香氨基酸衍生的代谢毒素在神经炎症中的作用

基本信息

批准号：
10446431
负责人：
Pavan Bhargava
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10446431
关键词：
Acetates Adrenergic Receptor Affect American Animal Model Antibiotics Antigen Presentation Aromatic Amino Acids Astrocytes Autoimmune B-Lymphocytes Behavioral Biological Assay Blood Blood Circulation Blood Platelets Cardiovascular Diseases Cell Count Cell Survival Cell physiology Cells Clinical Cresol Data Demyelinations Disease Dose Enzyme-Linked Immunosorbent Assay Etiology Experimental Autoimmune Encephalomyelitis Flow Cytometry Freund&apos s Adjuvant Functional disorder Funding Future G-Protein-Coupled Receptors Gene Expression Genome Glucuronides Goals Image Immune Immunization In Vitro Indoles Infiltration Inflammation Inflammatory Insulin Resistance Intervention Investigation Lead Link Measures Metabolic Metabolic Pathway Metabolism Microglia Mission Mitochondria Modeling Multiple Sclerosis Mus Myelin Myeloid Cells National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Neurosciences Research Oligodendroglia Outcome Pathogenesis Pathologic Peptides Persons Phenotype Phenylalanine Population Probiotics Process Production Public Health Reporting Research Retina Retinal Ganglion Cells Risk Role Sampling Serum Severities Severity of illness Sulfate Supplementation T-Lymphocyte Testing Therapeutic Intervention Thrombosis Toxic effect Toxin Tryptophan Tumor-infiltrating immune cells Tyrosine base beta-2 Adrenergic Receptors beta-adrenergic receptor cardiovascular risk factor cytokine dietary disability epigenome gut microbiota improved innovation insight macrophage metabolome metabolomics mitochondrial dysfunction mortality mouse model multiple sclerosis patient nervous system disorder neuroinflammation neurotoxic novel novel therapeutic intervention oligodendrocyte-myelin glycoprotein polarized cell research study response translational neuroscience young adult

项目摘要

Project Summary Multiple sclerosis (MS) is the most common neurodegenerative disease in young adults. Changes in the serum metabolome have been reported in MS and our preliminary data demonstrate that they are also associated with MS disease severity. We specifically show that aromatic amino acid (AAA)-derived metabolic toxins, produced by the gut microbiota, are associated with greater disease severity. Our long-term goals are to improve the understanding of the role of circulating metabolites in the pathophysiology of MS and discover novel therapeutic interventions based on those findings. The objectives of this R21 application are to determine whether AAA- derived metabotoxins have direct pro-inflammatory effects on immune and glial cells in vitro and also to determine whether treatment with these metabolites worsens neuroinflammation in a mouse model of MS. The rationale for this project, supported by preliminary data, is that people with MS have higher levels of these AAA- derived metabotoxins in their blood compared to healthy controls and the levels of these metabotoxins are correlated with disease severity measured clinically and by imaging measures. The proposed research study will pursue two specific aims: 1) to determine whether AAA-derived metabotoxins have pro-inflammatory effects on immune and glial cells in vitro; 2) To determine whether AAA-derived metabotoxins worsen the severity of neuroinflammation in an animal model of MS. For the first aim, we will test the effects of a variety of concentrations of four AAA-derived metabotoxins on pro-inflammatory polarization of adaptive (T and B cells) and innate (macrophages) immune cells, as well as glial cells (astrocytes and microglia). We will compare effects of various metabolites to vehicle and identify those that have pro-inflammatory effects (especially those with a dose-response relationship) without affecting cell viability. For the second aim, we will test the effects of supplementation with these AAA-derived metabotoxins on the severity of neuroinflammation in an animal model of MS – experimental autoimmune encephalomyelitis (EAE). We will utilize outcomes of inflammation (inflammatory cell infiltration and demyelination) and neurodegeneration (retinal ganglion cell counts in retinal flat mounts) in EAE mice. This will help provide complementary data to those generated in Aim 1. This project is innovative in that it proposes to test a novel hypothesis that metabolites in the circulation that are associated with MS disease severity may have direct effects on immune and glial cell function and may also affect neuroinflammation in an animal model of MS. The proposed research is significant because it can provide novel understanding of the mechanisms underlying MS disease pathogenesis and identifies new strategies for therapeutic interventions (such as dietary changes, probiotics, antibiotics and metabolite supplementation) for this common disabling neurological disorder.

项目摘要多发性硬化症（MS）是年轻人中最常见的神经退行性疾病。串行的变化代谢组已在MS中报道，我们的初步数据表明它们也与 MS疾病的严重程度。我们特别表明产生的芳香氨基酸（AAA）衍生的代谢毒素肠道菌群与疾病的严重程度更大有关。我们的长期目标是改善了解循环代谢物在MS的病理生理学中的作用并发现新型疗法基于这些发现的干预措施。该R21应用程序的目标是确定是否AAA- 衍生的代谢毒素在体外对免疫和神经胶质细胞具有直接促炎作用，也对确定用这些代谢物治疗是否会使MS小鼠模型中的神经炎症恶化。这该项目的基本原理在初步数据的支持下，有MS的人具有较高的这些AAA- 与健康对照组相比与通过临床和成像测量测量的疾病严重程度相关。拟议的研究将追求两个具体目标：1）确定AAA衍生的代谢毒素是否对体外免疫和神经胶质细胞； 2）确定AAA衍生的代谢毒素是否恶化 MS动物模型中的神经炎症。为了第一个目标，我们将测试各种四种AAA衍生的代谢毒素的浓度对自适应的促炎极化（T和B细胞）的浓度（T和B细胞）和先天性（巨噬细胞）免疫细胞以及神经胶质细胞（星形胶质细胞和小胶质细胞）。我们将比较效果各种代谢产物并识别具有促炎作用的代谢物（尤其是那些剂量反应关系）而不会影响细胞活力。为了第二个目标，我们将测试补充这些AAA衍生的代谢毒素，以对动物模型中神经炎症的严重程度进行补充 MS - 实验性自身免疫性脑脊髓炎（EAE）。我们将利用炎症的结果（炎症细胞浸润和脱髓鞘）和神经退行性（视网膜神经节细胞计数 eae小鼠中的平底山）。这将有助于向AIM 1中生成的数据提供完整的数据。此项目是创新的是，它提出了一个新的假设，即循环中的代谢产物与 MS疾病的严重程度可能会对免疫和神经胶质细胞功能产生直接影响，也可能影响 MS动物模型中的神经炎症。拟议的研究很重要，因为它可以提供新颖了解MS疾病发病机理的基础机制，并确定新的策略治疗干预措施（例如饮食变化，益生菌，抗生素和补充代谢物）这种常见的残疾神经系统疾病。