Bacterial triggers of neural inflammation.

神经炎症的细菌触发因素。

• 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
• 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

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.

项目总结/摘要 额颞叶痴呆（FTD）是一种进行性神经退行性疾病， 行为或语言，并最终导致记忆和认知严重受损。虽然在大多数情况下， FTD的病因尚不清楚，C9 ORF 72中的六核苷酸重复扩增是最常见的遗传原因 FTD和相关运动神经元疾病肌萎缩侧索硬化症（ALS）。不完全的 FTD/ALS高患病率家族中的C9 ORF 72突变表明，无论是遗传还是环境因素， 因素改变疾病风险。之前我们发现C9 orf 72功能缺失突变的小鼠经历了 FTD的神经炎性特征，如果在表现出明显 肠道中的微生物群落来自C9 orf 72突变小鼠所在环境的粪便物的测序 显示不同的健康结果使我们能够提名40种候选细菌物种， 在动物生病和死亡的环境中。在本提案的第一个目标中，我们将使用我们的代理 巨噬细胞细胞因子释放测定，以确定这40种候选细菌物种中的哪一种激活巨噬细胞因子。 炎症反应，因此可以指定2-3种细菌菌株进行功能随访。在第二个目标中， 我们将把促炎细菌移植到无菌的C9 orf 72突变小鼠体内， 神经炎症和CNS免疫豁免的丧失。我们的研究将有助于确定环境因素 这明显有助于观察到FTD患者表型和临床结局的异质性， 对选择最有可能受益于针对肠道微生物组的治疗的痴呆患者的见解。