Host - Microbe interactions in Parkinson's using a Caenorhabditis elegans (C. elegans)- Escherichia coli (E. coli) Holobiont Model

宿主 - 使用秀丽隐杆线虫 (C. elegans)-大肠杆菌 (E. coli) Holobiont 模型研究帕金森病中的微生物相互作用

• 批准号: 2274374
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2274374
• 关键词: Host; Microbe; interactions; Parkinson; using

PhD project strategic theme: Bioscience for an integrated understanding of healthParkinson's disease (PD) is a progressive neurological disorder that manifest itself through its gradual degenerative effects on the motor system of the nervous system. This clinical manifestation is pathologically derived from the abnormal accumulation and misfolding of a- Synuclein (aS), forming neurotoxic insoluble amyloid fibrils in Lewy bodies. This leads to the degradation of dopamine producing neurons in the substantia nigra of the brain. Resulting in the development of the still incurable and second most prevalent neurodegenerative disease, PD which is more prevalent amongst the ageing population, of above 65 years of age.Recent research provides evidence that signals peripheral to the central nervous system, particularly from the gastrointestinal tract and gut microbiota, are involved in the progression of PD. For example, aS pathology begins in peripheral tissues such as in the intestines and gradually spreads to multiple brain regions.The human gastrointestinal tract encompasses the densest microbial symbiotic ecosystem within the body. Altogether, these microbes which primarily constitute of bacteria produces over a 100 times more protein-coding genes than the human genome. Recently, cumulative evidence suggests that microbes harbored in the gastrointestinal tract are fundamental to the development and health of their host. For they aid in vitamin biosynthesis, improved energy and nutrient uptake through various metabolic pathways, and alleviate intestinal pathogen infections by helping develop and maturate the immune system providing a competitive environment for resources. The gut microbiota has also been shown to impact brain function by producing metabolites that enter the bloodstream. However, how gut bacteria affect aS aggregation is still unclear.To investigate the effect of microbiota in PD, we will use, Caenorhabditis elegans (C. elegans) as a model to demonstrate aS aggregation. C. elegans is an ideal model because its gut microbiota can be precisely controlled to study physiological processes at both the single-species and single-gene levels, and C. elegans has been validated as a valuable model of studying molecular mechanisms of Parkinson's disease and protein aggregation.Using a well-established C. elegans model of PD that expresses human aS in muscle cells. Phenotypic assays will be employed through the application of the E. coli KEIO Knockout Collection for all nonessential genes and the Phenomic Microarrays technology (Biolog), to respectively reveal the effects of bacterial genetic impairment and nutritional supplementation on the physiology of aS worms. Then, to further unravel the mechanisms underlying these interactions in the context of aS aggregation in the worms, RNA Sequencing, metabolomics, fluorescence recovery after photobleaching (FRAP), atomic force microscopy (AFM) and many more techniques will be employed for biological and biophysical characterisation of aS aggregation.Ultimately, host - microbe interactions in the context of aS could help to elucidate the processes involved in the protein aggregation associated in PD.

博士项目战略主题：帕金森病（PD）是一种渐进性神经系统疾病，通过对神经系统运动系统的逐渐退行性影响表现出来。这种临床表现在病理上源自α-突触核蛋白（aS）的异常积累和错误折叠，在路易体中形成神经毒性的不溶性淀粉样蛋白原纤维。这导致大脑黑质中产生多巴胺的神经元的降解。PD是一种仍然无法治愈的、第二常见的神经退行性疾病，在65岁以上的老龄化人群中更为普遍。最近的研究提供了证据表明，中枢神经系统的外周信号，特别是来自胃肠道的信号和肠道微生物群，参与了PD的进展。例如，aS病理开始于外周组织，如肠道，并逐渐扩散到多个大脑区域。人体胃肠道包含体内密集的微生物共生生态系统。总的来说，这些主要由细菌组成的微生物产生的蛋白质编码基因比人类基因组多100倍。最近，累积的证据表明，胃肠道中的微生物对其宿主的发育和健康至关重要。因为它们有助于维生素的生物合成，通过各种代谢途径改善能量和营养素的吸收，并通过帮助发展和成熟免疫系统来减轻肠道病原体感染，为资源提供竞争环境。肠道微生物群也被证明通过产生进入血液的代谢物来影响大脑功能。然而，肠道细菌如何影响aS聚集仍然不清楚。elegans）作为演示即服务聚合的模型。C.线虫是一个理想的模型，因为它的肠道微生物群可以精确地控制，以研究生理过程在单物种和单基因水平，和C。elegans已被证实是研究帕金森病和蛋白质聚集的分子机制的有价值的模型。在肌肉细胞中表达人aS的PD的elegans模型。将通过应用E. coli KEIO Knockout Collection的所有非必需基因和Phenomic Microarrays技术（Biolog），分别揭示细菌遗传损伤和营养补充对AS蠕虫生理的影响。然后，为了进一步揭示蠕虫中aS聚集背景下这些相互作用的机制，RNA测序、代谢组学、光漂白后荧光恢复（FRAP）、原子力显微镜（AFM）和更多技术将用于aS聚集的生物和生物物理表征。宿主-微生物相互作用的背景下，AS可能有助于阐明参与蛋白质聚集在PD相关的过程。