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， 环境相互作用导致α-突触核蛋白（α-突触核蛋白聚集）。最近的调查表明， 肠道微生物组可以调节对标志性α-突触核蛋白聚集的神经炎性反应，但很少 了解特定的肠道微生物介质。研究具有遗传性神经变性形式的罕见的kinkinases 这种与散发性疾病非常相似的疾病对该领域来说是非常宝贵的，为了解特发性 疾病在一个更可控的遗传和环境背景。我们正在调查环境 利用来自这样一个家庭的微生物组样本， 突触核蛋白（α-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， 在病理学上类似于这些疾病的散发形式。我们假设肠道微生物群 通过分泌影响神经炎症的代谢物来发展PDD/DLB 信号传导和神经元功能。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疾病相关，其中一些先前已报道在 警局其次，我们发现将PDD/DLB肠道微生物群转移到PD小鼠模型（具有扩增的E46>K 突变）增强运动和认知缺陷。第三，PDD/DLB微生物组转移改变了小胶质细胞 转录谱表明微生物群的变化可能有助于疾病的发病机制， 神经免疫调节在这项提案中，我们的目标是确定微生物和代谢物， 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 在PDD/DLB诱导的多能干细胞（iPSC）衍生的培养物中体外的功能和神经元存活。第一、 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 确定肠道宏基因组和代谢物的变化，分析改变的小胶质细胞转录谱， 评估PDD/DLB-微生物群定殖的小鼠中的α-突触核蛋白病理学，当与PDD/DLB-微生物群定殖的小鼠相比时， 健康对照或CNS无症状E46 K携带者微生物组。第二，确定影响 微生物代谢产物对PDD/DLB相关通路的影响，我们将治疗E46 K PDD/DLB患者和基因 用来自内部分离的细菌上清液校正iPSC衍生的小胶质细胞和神经元培养物 在E46 K PDD/DLB个体中丰富的微生物物种，或来自细菌致敏的小胶质细胞的培养基。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、神经突 生长和存活，以及α-突触核蛋白病理学，以确定PDD/DLB微生物的机制影响。 代谢物对体外可变疾病转移率的影响。所获得的知识和建立的模型系统， 这个R21的建议可能最终有助于理解影响人类健康的分子和代谢功能， 为进一步研究PD和PD痴呆的发病机制提供了重要的生物学资源。