Investigating how the microbiota modulates neuroinflammatory signaling and neurodegeneration in Parkinson's disease and dementia

研究微生物群如何调节帕金森病和痴呆症的神经炎症信号传导和神经退行性变

• 批准号: 10575564
• 负责人: Laura Michelle Cox
• 金额: $ 48.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10575564
• 关键词: Affect; Alzheimer' s disease related dementia; Animals; Bacteria; Biological; Biological Models; Cecum; Cell Line; Clinical; Cognitive; Cognitive deficits; Complex; Data; Dementia; Dementia with Lewy Bodies; Development; Disease; Disease Outcome; Environment; Exhibits; Family; Family member; Future; Gene Expression Profile; Genes; Genetic; Histopathology; Human; Idiopathic Parkinson Disease; In Vitro; Individual; Inflammatory; Inherited; Investigation; Knowledge; Lead; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Light; Link; Measures; Mediator of activation protein; Metabolic; Microbe; Microglia; Modeling; Molecular; Motor; Mus; Mutation; Nerve Degeneration; Neurites; Neuroimmune; Neurologic; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Penetrance; Process; Proteins; Reporting; Research; Resources; Sampling; Serum; Signal Transduction; Symptoms; Testing; Time; alpha synuclein; base; behavior test; brain tissue; chemokine; clinical phenotype; cognitive function; cytokine; gene correction; gut metagenome; gut microbiome; gut microbiota; gut-brain axis; in vitro Model; in vivo; in vivo Model; induced pluripotent stem cell; kindred; lens; microbial; microbiome; microbiota; motor deficit; mouse model; neuroinflammation; neuronal survival; neuropathology; novel; novel therapeutics; overexpression; response; sex; stem cell model; synucleinopathy

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are complex diseases involving gene- environment interplay that lead to alpha-synuclein (a-synuclein aggregation). Recent investigations suggest that the gut microbiome can modulate neuroinflammatory responses to hallmark a-synuclein aggregation, but little is known about specific gut microbial mediators. Studying rare kindreds with inherited forms of neurodegeneration that closely mimic sporadic disease has proved invaluable to the field, offering a window to understand idiopathic disease in a more controlled genetic and environmental background. We are investigating environmental determinants of disease penetrance utilizing microbiome samples from such a family harboring an alpha- synuclein (a-synuclein) E46>K mutation and exhibiting a spectrum of clinical PD dementia (PDD)/DLB outcomes, that pathologically mimic sporadic forms of these diseases. We hypothesize that gut microbiota contributes to the development of PDD/DLB through the secretion of metabolites that affect neuroinflammatory signaling and neuronal function. In our preliminary data, first we identified specific bacterial species associated with PDD/DLB disease penetrance, some of which have been previously reported to be altered in PD. Second, we found that transfer of the PDD/DLB gut microbiota into a PD mouse model (with amplified E46>K mutation) enhanced motor and cognitive deficits. Third, PDD/DLB microbiome transfer altered microglial transcriptional profiles suggesting that changes in microbiota could contribute to disease pathogenesis through neuroimmune modulation. In this proposal, we aim to identify microbes and metabolites which are linked with PDD/DLB pathogenesis using in vivo models and evaluate whether these metabolites directly affect microglial function and neuronal survival in vitro in PDD/DLB induced pluripotent stem cell (iPSC)-derived cultures. First, to investigate potential gut-brain axis mechanisms associated with altered motor and cognitive function, we will identify changes in the gut metagenome and metabolites, analyze altered microglia transcriptional profiles and evaluate a-synuclein pathology in PDD/DLB-microbiota colonized mice, when compared to mice colonized with either healthy control or CNS asymptomatic E46K carrier microbiome. Second, to determine the impact of microbial metabolites on pathways involved in PDD/DLB, we will treat E46K PDD/DLB patient and gene corrected iPSC-derived microglia and neuronal cultures with either bacterial supernatants from in-house isolated microbial species abundant in E46K PDD/DLB individuals, or media from bacteria-sensitized microglia. We will evaluate the neuroinflammatory cytokine and chemokine profile, microglia transcriptional profiles, neurite outgrowth and survival, and a-synuclein pathology to determine the mechanistic impact of PDD/DLB microbial metabolites on variable disease penetrance in vitro. The knowledge gained and model systems established in this R21 proposal may ultimately contribute to the understanding of molecular and metabolic functions that affect PD and PD dementia and provide essential biologic resources for future mechanistic study.

帕金森病 (PD) 和路易体痴呆 (DLB) 是涉及基因的复杂疾病 最近的研究表明，环境相互作用会导致 α-突触核蛋白（α-突触核蛋白聚集）。 肠道微生物组可以调节标志性α-突触核蛋白聚集的神经炎症反应，但很少有 研究具有遗传性神经退行性疾病的罕见家族。 事实证明，这种密切模仿散发性疾病的方法对该领域具有无价的价值，为了解特发性疾病提供了一个窗口 在更受控制的遗传和环境背景下发生疾病我们正在研究环境。 利用来自携带α-的家族的微生物组样本确定疾病外显率的决定因素 突触核蛋白（a-突触核蛋白）E46>K 突变并表现出一系列临床 PD 痴呆 (PDD)/DLB 结果， 我们追寻肠道微生物群在病理上模仿这些疾病的散发形式。 通过分泌影响神经炎症的代谢物来促进 PDD/DLB 的发展 在我们的初步数据中，我们首先确定了特定的细菌种类。 与 PDD/DLB 疾病外显率相关，其中一些此前已被报道在 其次，我们发现将 PDD/DLB 肠道微生物群转移到 PD 小鼠模型中（E46>K 扩增）。 第三，PDD/DLB 微生物组转移改变了小胶质细胞。 转录谱表明微生物群的变化可能通过以下方式促进疾病发病机制 在本提案中，我们的目标是识别与神经免疫调节相关的微生物和代谢物。 使用体内模型研究 PDD/DLB 发病机制并评估这些代谢物是否直接影响小胶质细胞 PDD/DLB 诱导的多能干细胞 (iPSC) 衍生培养物中的功能和神经存活 为了研究与运动和认知功能相关的潜在肠脑轴机制，我们将 识别肠道宏基因组和代谢物的变化，分析小胶质细胞转录谱并 与定植有PDD/DLB微生物群的小鼠相比，评估α-突触核蛋白病理学 无论是健康对照还是中枢神经系统无症状E46K携带者微生物组第二，确定影响。 微生物代谢物对PDD/DLB相关途径的影响，我们将治疗E46K PDD/DLB患者和基因 使用内部分离的细菌上清液校正 iPSC 衍生的小胶质细胞和神经培养物 E46K PDD/DLB 个体中丰富的微生物物种，或来自细菌敏感的小胶质细胞的培养基。 评估神经炎症细胞因子和趋化因子谱、小胶质细胞转录谱、神经突 生长和存活，以及 a-突触核蛋白病理学，以确定 PDD/DLB 微生物的机械影响 体外不同疾病外显率的代谢物获得的知识和建立的模型系统。 这个 R21 提案可能最终有助于理解影响的分子和代谢功能 PD和PD痴呆症并为未来的机制研究提供必要的生物资源。