A humanized mouse model to analyse the age-dependent impact of gut microbiota on microglial diversity in the brain

人源化小鼠模型，用于分析肠道微生物群对大脑小胶质细胞多样性的年龄依赖性影响

• 批准号: 500012302
• 负责人: Dr. Christiane Frahm
• 金额: --
• 依托单位: Institut für Experimentelle Medizin (IEM)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/500012302?language=en
• 关键词: humanized; mouse; model; analyse; age

Cognitive decline and dementia are among the most important aging-related health problems worldwide. A key component of aging-associated neurodegeneration is a low-grade systemic inflammation (inflammaging), which in the brain is mainly mediated by activated microglia. Recently, it has been discovered that the microglia receive signals from intestinal microbes as well as their metabolic products and react to them. This highlights microbiota-microglia interactions as an attractive therapeutic target for therapies attenuating inflammaging. The aim of this project is to create a human microbiota-associated mouse model to establish a causal link between the human intestinal microbiota and microglial cell function and diversity. We expect an improvement of cognitive function based on microglial anti-inflammatory and neuro-supportive function in old mice after transfer of microbiota derived from young healthy donors, and vice versa a pro-inflammatory microglial phenotype associated with cognitive dysfunctions in young mice after transfer of microbiota from old donors. Single cell sequencing of hippocampi will determine changes in microglial heterogeneity and gene expression. In particular, microglia will be analysed with respect to the regulation of inflammatory genes and on that basis sorted into cellular subtypes. In addition, we will provide immunohistochemical evidence of their morphological activation state. In order to causally link the microbiota to microglial function and diversity, we will use a novel modelling approach to identify microbiota-produced metabolites that influence microglial heterogeneity. The functional relevance of these peripherally produced metabolites will be validated in cell cultures of primary microglia. In the future, our new pre-clinical animal model and modelling approach should serve as an essential basis for the rational design of microbiome-based therapies to counteract microglia-mediated aging-associated neurodegeneration.

认知能力下降和痴呆是世界范围内与衰老相关的最重要的健康问题。衰老相关神经退行性变的一个关键组成部分是低度全身性炎症（炎症），其在大脑中主要由活化的小胶质细胞介导。近年来，人们发现小胶质细胞接受肠道微生物及其代谢产物的信号并对其作出反应。这突出了微生物-小胶质细胞相互作用作为治疗减轻炎症的一个有吸引力的治疗靶点。本项目旨在建立人类微生物群相关小鼠模型，以建立人类肠道微生物群与小胶质细胞功能和多样性之间的因果关系。我们预计，移植来自年轻健康供体的微生物群后，老年小鼠基于小胶质细胞抗炎和神经支持功能的认知功能得到改善，反之亦然，移植来自老年供体的微生物群后，年轻小鼠的促炎小胶质细胞表型与认知功能障碍相关。海马单细胞测序将决定小胶质异质性和基因表达的变化。特别是，将分析小胶质细胞对炎症基因的调节，并在此基础上分类为细胞亚型。此外，我们将提供其形态激活状态的免疫组织化学证据。为了将微生物群与小胶质细胞的功能和多样性联系起来，我们将使用一种新的建模方法来鉴定影响小胶质细胞异质性的微生物群产生的代谢物。这些外周产生的代谢物的功能相关性将在初级小胶质细胞培养中得到验证。在未来，我们新的临床前动物模型和建模方法应该作为合理设计微生物组为基础的疗法，以对抗小胶质细胞介导的衰老相关神经变性的重要基础。