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:
- 金额:$ 19.42万
- 依托单位:
- 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:
- 关键词:AblationAddressAdoptive TransferAffectAlcohol consumptionAlcohol dependenceAlcoholsAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectAstrocytesAutoimmune DiseasesAutomobile DrivingBasic ScienceBioinformaticsBiologyBlood - brain barrier anatomyCNS Demyelinating Autoimmune DiseasesCaringCellsCentral Nervous SystemChronicClinicalClinical Investigator AwardCommunicationConsumptionCritical PathwaysDataDevelopmentDietDietary FactorsDiseaseDisease OutcomeDoseEnvironmental ExposureEnvironmental Risk FactorEtiologyExperimental Autoimmune EncephalomyelitisFirmicutesFlow CytometryFoundationsFundingFutureGenesGeneticGerm-FreeImmuneImmune responseImmune systemImmunohistochemistryImmunologyIndividualInflammatoryInvestigationLeadLinkMediatingMentorsMentorshipMicrogliaModelingMultiple SclerosisMusNerve DegenerationNeurobiologyNeuroimmuneNeurologicNeurologyOutcomePatientsPatternPeripheralPeripheral Nervous SystemPersonsPhenotypePhysiciansPredispositionProbioticsProgram DevelopmentRegulatory T-LymphocyteResearchRiskRoleScientistSex DifferencesSpinal CordSymptomsSystemT cell therapyT-LymphocyteTestingTherapeuticTrainingVisionVocational GuidanceWorkabuse liabilityalcohol effectalcohol researchaustinbinge drinkingcareer developmentclinical trainingdensitydesigndietarydisabilitydisorder riskenzyme linked immunospot assayepidemiology studyevidence baseexperienceexperimental studygut microbiomegut microbiotagut-brain axisinsightmalemedical schoolsmicrobialmicrobiomemicrobiome researchmicrobiotamouse modelmultiple sclerosis patientneuroimmunologyneuroinflammationneuroprotectionprofessorsexsexual dimorphismtranscriptome sequencingtranscriptomicstreatment responseyoung 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.
该提案提出了一项专注于酒精研究的研究职业发展计划
多发性硬化症 (MS) 小鼠模型神经炎症的剂量依赖性效应,实验
我目前是戴尔医疗中心的神经病学助理教授。
德克萨斯大学奥斯汀分校的学校概述的提案建立在我之前对性神经生物学的研究的基础上。
差异,神经免疫学的临床培训并整合生物信息学的新专业领域,
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 Adron Harris 博士(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、教学和指导将使我能够过渡到 R01 资助的项目
神经免疫学和酒精研究跨学科领域的医师科学家。
MS 是一种中枢神经系统 (CNS) 的慢性自身免疫性脱髓鞘疾病
导致年轻人神经功能障碍的主要原因是多发性硬化症(MS)的原因尚不清楚。
基因会导致疾病风险,人们认为饮食和肠道等环境因素
微生物组对风险的影响更大。酒精是多发性硬化症常见的饮食因素。
然而,尽管它被广泛使用、有滥用的可能性以及已知的肠道、中枢神经系统和免疫影响,
酒精在多发性硬化症中的作用尚不清楚,该提案的基础是基于我的初步研究。
PNAS 发表的研究表明,适量饮酒可改善 EAE,
脊髓中小胶质细胞的减少,以及肠道微生物群向调节表型的转变
性别特异性模式,共同表明适量饮酒对 EAE 和潜在的 EAE 具有保护作用
鉴于酒精已知的促炎作用,这些研究提出了酒精可能的问题。
高剂量和中等剂量对神经炎症的不同影响该提案开始解决这个问题。
通过评估酒精对外周和中枢神经系统免疫系统的剂量依赖性影响来回答这个问题
具体来说,该提案的目标是(1)什么是外周和中枢神经系统免疫。
细胞亚群驱动 EAE 中的剂量依赖性酒精效应?能否从饮酒中进行过继转移?
小鼠重现了幼鼠的临床症状?(2)哪些肠道微生物组成分是
酒精对 EAE 的剂量依赖性影响是由酒精引起的吗?
小鼠重现幼鼠的临床症状?该提案的科学目标是开始
通过检查免疫系统和肠道来确定酒精对神经炎症的剂量依赖性影响
微生物组的愿景是产生可以为未来饮食的方向和设计提供信息的假设
EAE 和 MS 的研究,并为 MS 患者扩展可用的和有针对性的益生菌。
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)
Longitudinal COVID-19 immune trajectories in patients with neurological autoimmunity on anti-CD20 therapy.
接受抗 CD20 治疗的神经性自身免疫患者的纵向 COVID-19 免疫轨迹。
- DOI:
- 发表时间:2022-12
- 期刊:
- 影响因子:0
- 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
Lupus and NMOSD: The Blending of Humoral Autoimmunity.
狼疮和 NMOSD:体液自身免疫的混合。
- DOI:
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Ochi, Maria Goretti S;Shapiro, Samantha C;Melamed, Esther
- 通讯作者:Melamed, Esther
Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder.
视神经脊髓炎谱系疾病中循环 Aquaporin-4 抗体的分子水平表征。
- DOI:
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Li, Jie;Bazzi, Sam A;Schmitz, Florian;Tanno, Hidetaka;McDaniel, Jonathan R;Lee, Chang;Joshi, Chaitanya;Kim, Jin Eyun;Monson, Nancy;Greenberg, Benjamin M;Hedfalk, Kristina;Melamed, Esther;Ippolito, Gregory C
- 通讯作者:Ippolito, Gregory C
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:
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Maguire, Cole;Frohman, Teresa;Zamvil, Scott S;Frohman, Elliot;Melamed, Esther
- 通讯作者:Melamed, Esther
Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 2: From the National Multiple Sclerosis Society Case Conference Proceedings.
PML 幸存后治疗 MS:患者 2 的抢救、缓解和康复的离散策略:来自国家多发性硬化症协会病例会议记录。
- DOI:
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Cruz, Roberto Alejandro;Hogan, Nick;Sconzert, Jayne;Sconzert, Megan;Major, Eugene O;Lisak, Robert P;Melamed, Esther;Varkey, Thomas C;Meltzer, Ethan;Goodman, Andrew;Komogortsev, Oleg;Parsons, Matthew S;Costello, Kathleen;Graves, Jennifer S;Ne
- 通讯作者:Ne
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Esther Melamed其他文献
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{{ truncateString('Esther Melamed', 18)}}的其他基金
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
- 批准号:
10055316 - 财政年份:2020
- 资助金额:
$ 19.42万 - 项目类别:
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
- 批准号:
10228072 - 财政年份:2020
- 资助金额:
$ 19.42万 - 项目类别:
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
- 批准号:
10456826 - 财政年份:2020
- 资助金额:
$ 19.42万 - 项目类别:
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