Bacterial triggers of neural inflammation.

神经炎症的细菌触发因素。

基本信息

批准号：
10571564
负责人：
Aaron Burberry
金额：
$ 16.1万
依托单位：
CASE WESTERN RESERVE 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：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10571564
关键词：
Adult Affect Amyotrophic Lateral Sclerosis Animals Bacteria Behavior Biological Assay Brain C9ORF72 Cells Central Nervous System Chromosome 9 Clinical Cognition Data Set Dementia Diagnosis Dipeptides Disease Environment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Etiology Exposure to Failure Family Feces Flow Cytometry Frontotemporal Dementia Future Genes Genetic Genetic Transcription Genotype Germ-Free Health Heterogeneity High Prevalence Human Immune Immune system Individual Infiltration Inflammatory Inflammatory Response Inherited Intervention Language Lobe Macrophage Mass Spectrum Analysis Memory impairment Microbe Motor Neuron Disease Mus Mutant Strains Mice Mutation Nerve Degeneration Nervous System Neurodegenerative Disorders Open Reading Frames Organism Outcome Pathway interactions Patients Penetrance Peripheral Persons Phenotype Plasma Pre-Clinical Model Production Proteins Proxy Publishing RNA Research Semantics Syndrome T cell infiltration TNF gene Therapeutic Translations Transplantation United States brain tissue cell type chemokine cytokine disorder risk experience experimental study fecal transplantation follow-up frontotemporal lobar dementia amyotrophic lateral sclerosis gene product glial activation gut bacteria gut microbiome inflammatory milieu insight interest loss of function loss of function mutation metabolomics microbial community mouse model multiplex assay mutant neural neuroinflammation neuron loss neutrophil personalized medicine premature response screening targeted treatment trafficking

项目摘要

Project Summary/Abstract Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that starts with alterations in behavior or language and culminates in severe impairment of memory and cognition. While in most cases the etiology of FTD is unclear, a hexanucleotide repeat expansion in C9ORF72 is the most common inherited cause of FTD and the related motor neuron disease Amyotrophic lateral sclerosis (ALS). Incomplete penetrance of the C9ORF72 mutation in families with high prevalence of FTD/ALS indicates that either genetic or environmental factors modify disease risk. Previously we found that mice with loss of function mutations in C9orf72 experienced the neural inflammatory features of FTD and died if they were raised in environments that displayed distinct microbial communities in their gut. Sequencing of fecal matter from environments where C9orf72 mutant mice displayed divergent health outcomes allowed us to nominate 40 candidate bacterial species that were enriched in the environments where animals got sick and died. In the first Aim of this proposal, we will use our proxy macrophage cytokine release assay to determine which of these 40 candidate bacterial species activate an inflammatory response so that 2-3 bacterial strains can be nominated for functional follow-up. In the second Aim, we will transplant pro-inflammatory bacteria into germ-free C9orf72 mutant mice to identify strains that trigger neural inflammation and loss of CNS immune privilege. Our studies will help to identify environmental factors that credibly contribute to observed heterogeneity in FTD patient phenotype and clinical outcome and provide insight towards selection of dementia patients most likely to benefit from therapies that target the gut microbiome.

项目摘要/摘要额颞痴呆（FTD）是一种进行性神经退行性疾病，始于改变行为或语言，并在严重损害记忆力和认知方面达到顶点。在大多数情况下 FTD的病因尚不清楚，C9orf72中的六核苷酸重复扩展是最常见的遗传原因 FTD和相关的运动神经元疾病肌萎缩性侧硬化症（ALS）。不完整的渗透率 FTD/ALS患病率高的家族中的C9ORF72突变表明遗传或环境因素改变了疾病的风险。以前，我们发现C9orf72中有功能突变损失的小鼠经历了 FTD的神经炎症特征，如果它们在显示不同的环境中抬高，则死亡肠道中的微生物群落。从C9orf72突变小鼠的环境中对粪便的测序显示出不同的健康结果使我们得名40种富含的候选细菌物种在动物生病并死亡的环境中。在该提案的第一个目的中，我们将使用代理巨噬细胞细胞因子释放测定法确定这40种候选细菌种类中的哪个激活炎症反应，因此可以提名2-3个细菌菌株进行功能随访。在第二个目标中我们将促炎细菌移植到无细菌C9orf72突变小鼠中，以鉴定触发的菌株神经炎症和CNS免疫特权的丧失。我们的研究将有助于确定环境因素这极大地有助于观察到的FTD患者表型和临床结果的异质性，并提供洞察痴呆症患者最有可能受益于针对肠道微生物组的疗法。