Bacterial triggers of neural inflammation.

项目摘要/摘要 额颞叶痴呆(FTD)是一种进行性神经退行性疾病，以 行为或语言，最终导致记忆和认知的严重损害。而在大多数情况下， FTD的病因尚不清楚，C9ORF72中的六核苷酸重复序列扩张是最常见的遗传原因 FTD和相关运动神经元病肌萎缩侧索硬化症(ALS)。不完整的外显性 FTD/ALS高发家系C9ORF72突变提示遗传或环境因素 影响疾病风险的因素。之前我们发现C9orf72功能突变丧失的小鼠经历了 FTD和死亡的神经炎性特征在明显不同的环境中生长 肠道中的微生物群落。C9orf72突变小鼠环境中粪便物质的测序 通过展示不同的健康结果，我们提名了40种候选细菌，这些细菌都是丰富的 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试验确定这40种候选细菌中的哪一种激活了 炎症反应，使2-3个细菌菌株可被提名进行功能随访。在第二个目标中， 我们将把促炎细菌移植到无菌C9orf72突变小鼠中，以鉴定引发 神经炎症和中枢神经系统免疫特免权丧失。我们的研究将有助于确定环境因素 可信地有助于观察到FTD患者表型和临床结果的异质性，并提供 洞察选择最有可能从针对肠道微生物群的治疗中受益的痴呆症患者。

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.