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.

帕金森氏病（PD）和Lewy身体（DLB）是涉及基因的复杂疾病 导致α-突触核蛋白（A-突触核蛋白聚集）的环境相互作用。最近的投资表明 肠道微生物组可以调节对Hallmark A-核蛋白聚集的神经炎症反应，但几乎没有 有关特定肠道微生物介质的已知。研究具有遗传形式的神经变性形式的稀有亲属 这种紧密模仿的零星疾病已被证明对该领域非常宝贵，提供了一个理解特发性的窗口 在更受控的遗传和环境背景下的疾病。我们正在调查环境 利用微生物组样本的疾病渗透率的决定因素，该家族带有α- 综合蛋白（A-核蛋白）E46> k突变并表现出一系列临床PD痴呆（PDD）/DLB结果， 这些疾病的病理模仿零星形式。我们假设肠道菌群有助于 通过影响神经炎症的代谢产物的分泌来开发PDD/DLB 信号传导和神经元功能。在我们的初步数据中，首先我们确定了特定的细菌物种 与PDD/DLB疾病渗透相关 PD。其次，我们发现将PDD/DLB肠道微生物群转移到PD小鼠模型中（带有放大器E46> k 突变）增强了运动和认知缺陷。第三，PDD/DLB微生物组转移改变了小胶质细胞 转录曲线表明，微生物群的变化可能会导致疾病发病机理 神经免疫调节。在此提案中，我们旨在确定与之相关的微生物和代谢物 使用体内模型的PDD/DLB发病机理，并评估这些代谢物是否直接影响小胶质细胞 PDD/DLB诱导多能干细胞（IPSC）衍生的培养物中的功能和神经元存活。第一的， 为了研究与运动和认知功能改变相关的潜在肠脑轴机制，我们将 确定肠道元基因组和代谢物的变化，分析改变的小胶质细胞转录曲线和 与与用小鼠一起定殖的小鼠，评估PDD/DLB-微生物群中的A-核蛋白病理学。 健康对照或中枢神经系统不对称的E46K载体微生物组。第二，确定 在涉及PDD/DLB的途径上的微生物代谢物，我们将处理E46K PDD/DLB患者和基因 校正了IPSC衍生的小胶质细胞和神经元培养物，具有内部分离的两种细菌上清液 E46K PDD/DLB个体中丰富的微生物物种，或细菌敏感的小胶质细胞中的培养基。我们将 评估神经炎性细胞因子和趋化因子谱，小胶质细胞转录谱，神经蛋白 生存和生存，以及A-核蛋白病理学，以确定PDD/DLB微生物的机械影响 体外疾病渗透性的代谢产物。获得的知识和建立的模型系统 该R21提案最终可能有助于理解影响分子和代谢功能 PD和PD痴呆症，为未来的机械研究提供基本的生物资源。