Alcohol's Impact on the Gut-Brain Axis in a Mouse Model of Multiple Sclerosis

酒精对多发性硬化症小鼠模型肠脑轴的影响

基本信息

批准号：
10674807
负责人：
Esther Melamed
金额：
$ 19.42万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-05 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674807
关键词：
Ablation Address Adoptive Transfer Affect Alcohol consumption Alcohol dependence Alcohols Animals Anti-Inflammatory Agents Antiinflammatory Effect Astrocytes Autoimmune Diseases Automobile Driving Basic Science Bioinformatics Biology Blood - brain barrier anatomy CNS Demyelinating Autoimmune Diseases Caring Cells Central Nervous System Chronic Clinical Clinical Investigator Award Communication Consumption Critical Pathways Data Development Diet Dietary Factors Disease Disease Outcome Dose Environmental Exposure Environmental Risk Factor Etiology Experimental Autoimmune Encephalomyelitis Firmicutes Flow Cytometry Foundations Funding Future Genes Genetic Germ-Free Immune Immune response Immune system Immunohistochemistry Immunology Individual Inflammatory Investigation Lead Link Mediating Mentors Mentorship Microglia Modeling Multiple Sclerosis Mus Nerve Degeneration Neurobiology Neuroimmune Neurologic Neurology Outcome Patients Pattern Peripheral Peripheral Nervous System Persons Phenotype Physicians Predisposition Probiotics Program Development Regulatory T-Lymphocyte Research Risk Role Scientist Sex Differences Spinal Cord Symptoms System T cell therapy T-Lymphocyte Testing Therapeutic Training Vision Vocational Guidance Work abuse liability alcohol effect alcohol research austin binge drinking career development clinical training density design dietary disability disorder risk enzyme linked immunospot assay epidemiology study evidence base experience experimental study gut microbiome gut microbiota gut-brain axis insight male medical schools microbial microbiome microbiome research microbiota mouse model multiple sclerosis patient neuroimmunology neuroinflammation neuroprotection professor sex sexual dimorphism transcriptome sequencing transcriptomics treatment response young adult

项目摘要

This proposal presents a research career development program focused on the study of alcohol’s dose-dependent effects in neuroinflammation in a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). I am currently an assistant professor of neurology at Dell Medical School at UT Austin. The outlined proposal builds on my previous research in neurobiology of sex differences, clinical training in neuroimmunology and integrates new domains of expertise in bioinformatics, alcohol and microbiome research, and basic science neuroimmunology. I will be guided by outstanding mentors and advisors, including Drs. Adron Harris (alcohol research), Hans Hofmann (bioinformatics), Sergio Baranzini (microbiome), Olaf Stuve (neuroimmunology), and William Schwartz (career guidance). The proposed experiments, didactics, and mentorship will enable me to transition to an R01 funded physician scientist in the cross disciplinary field of neuroimmunology and alcohol research. MS is a chronic autoimmune demyelinating disease of the central nervous system (CNS) and the leading acquired cause of neurological disability in young adults. The cause of MS is unknown. Although genes contribute to the disease risk, it is thought that environmental factors, such as diet and the gut microbiome contribute to a larger degree of the risk. Alcohol is a common dietary factor used by MS patients. Yet, despite its widespread use, potential for abuse and known gut, CNS and immune effects, alcohol’s role in MS is not well understood. The foundation of this proposal is based on my preliminary studies, in press in PNAS, demonstrating that moderate alcohol consumption leads to EAE amelioration, decrease in microglia in the spinal cord, and a shift of gut microbiota toward a regulatory phenotype in a sex-specific pattern, that collectively suggest a protective role of moderate alcohol in EAE and potentially in MS. Given known pro-inflammatory effects of alcohol, these studies raise the question of alcohol’s possible differential effects on neuroinflammation at high vs moderate doses. This proposal begins to address this question by evaluating alcohol’s dose-dependent effects on the peripheral and CNS immune system and the gut microbiome. Specifically, the aims of this proposal are (1) What are the peripheral and CNS immune cell subsets driving dose-dependent alcohol effects in EAE? Can adoptive transfer from alcohol-consuming mice recapitulate clinical symptoms in naive mice? and (2) Which gut microbiome constituents are responsible for alcohol’s dose-dependent effects in EAE? Can microbiome transfer from alcohol-consuming mice recapitulate clinical symptoms in naive mice? The scientific objective of this proposal is to begin to define alcohol’s dose-dependent effects in neuroinflammation by examining the immune system and the gut microbiome with the vision of generating hypotheses that can inform the direction and design of future diet studies in EAE and MS and expand the repertoire of available and targeted probiotics for MS patients.

该建议提出了一项研究职业发展计划，重点是研究酒精的研究多发性硬化症（MS）的小鼠模型中的神经炎症剂量依赖性作用，实验自身免疫性脑脊髓炎（EAE）。我目前是戴尔医学的神经病学助理教授在UT Austin上学。概述的提案是基于我以前在性爱神经生物学研究的基础上的差异，神经免疫学方面的临床培训，并整合了生物信息学专业知识的新领域，酒精和微生物组研究以及基础科学神经免疫学。我将受到杰出的指导导师和顾问，包括Drs。 Adron Harris（酒精研究），Hans Hofmann（生物信息学）， Sergio Baranzini（微生物组），Olaf Stuve（神经免疫学）和William Schwartz（职业指导）。拟议的实验，教学法和精神训练将使我能够过渡到R01资助的R01 神经免疫学和酒精研究的跨学科领域的医师科学家。 MS是中枢神经系统（CNS）和年轻人的主要因果神经残疾的原因。 MS的原因是未知的。虽然基因导致疾病风险，人们认为环境因素（例如饮食和肠道）微生物组有助于更大程度的风险。酒精是MS使用的常见饮食因素患者。然而，dospite的宽度使用，滥用和已知肠道，中枢神经系统和免疫效应的潜力，酒精在MS中的作用尚不清楚。该提议的基础是基于我的初步研究在PNAS中的研究表明，适度的饮酒会导致EAE改善，脊髓中小胶质细胞的降低，并将肠道菌群转移到A中的调节表型性别特定的模式，共同提出了现代化酒精在EAE中的受保护作用，并可能在多发性硬化症。鉴于已知的酒精促炎作用，这些研究提出了酒精的问题在高与中等国内剂量下对神经炎症的差异影响。该建议开始解决这个问题通过评估酒精对外围和中枢神经系统免疫系统的剂量依赖性影响以及肠道微生物组。具体而言，该提案的目的是（1）外围和CNS免疫是什么细胞集在EAE中驱动剂量依赖性酒精效应？可以从饮酒中适应转移小鼠概括了天真小鼠的临床症状？（2）哪个肠道微生物组构成负责酒精对EAE的剂量依赖性影响？微生物组可以从饮酒中转移小鼠概括了天真小鼠的临床症状？该提议的科学目标是开始通过检查免疫系统和肠道，定义酒精对神经炎症的剂量依赖性作用微生物组的愿景具有产生可以告知未来饮食方向和设计的假设在EAE和MS的研究中，扩大了MS患者的可用益生菌和靶向益生菌的曲目。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Should interferons take front stage as an essential MS disease-modifying therapy in the era of coronavirus disease 2019?

在 2019 年冠状病毒病时代，干扰素是否应该成为重要的多发性硬化症疾病缓解疗法？

DOI：
10.1212/nxi.0000000000000811
发表时间：
2020
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
0
作者：
Maguire,Cole;Frohman,Teresa;Zamvil,ScottS;Frohman,Elliot;Melamed,Esther
通讯作者：
Melamed,Esther

Advantages and limitations of experimental autoimmune encephalomyelitis in breaking down the role of the gut microbiome in multiple sclerosis.

DOI：
10.3389/fnmol.2022.1019877
发表时间：
2022
期刊：
FRONTIERS IN MOLECULAR NEUROSCIENCE
影响因子：
4.8
作者：
Melamed, Esther;Palmer, Jamie L.;Fonken, Cara
通讯作者：
Fonken, Cara

Longitudinal COVID-19 immune trajectories in patients with neurological autoimmunity on anti-CD20 therapy.

DOI：
10.1016/j.msard.2022.104195
发表时间：
2022-12
期刊：
MULTIPLE SCLEROSIS AND RELATED DISORDERS
影响因子：
4
作者：
Bazzi, Sam A.;Maguire, Cole;Holay, Nisha;Geltman, Janelle;Hurley, Kerin;DiPasquale, Chris;Abigania, Melissa;Olson, Eric;Ehrlich, Lauren I. R.;Triplett, Todd A.;Melamed, Esther
通讯作者：
Melamed, Esther

Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder.

DOI：
10.1212/nxi.0000000000001034
发表时间：
2021-07
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
0
作者：
Li J;Bazzi SA;Schmitz F;Tanno H;McDaniel JR;Lee CH;Joshi C;Kim JE;Monson N;Greenberg BM;Hedfalk K;Melamed E;Ippolito GC
通讯作者：
Ippolito GC

Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 2: From the National Multiple Sclerosis Society Case Conference Proceedings.

DOI：
10.1212/nxi.0000000000000930
发表时间：
2021-01
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
0
作者：
Cruz RA;Hogan N;Sconzert J;Sconzert M;Major EO;Lisak RP;Melamed E;Varkey TC;Meltzer E;Goodman A;Komogortsev O;Parsons MS;Costello K;Graves JS;Newsome S;Zamvil SS;Frohman EM;Frohman TC
通讯作者：
Frohman TC