Integrated PhD Biomedical Science

阿尔茨海默病(AD)是一种慢性神经退行性疾病，其特征是蛋白异常堆积，表现为β-淀粉样斑块和tau缠结。大多数AD病例是散发性的，具有多因素基础，表现为遗传易感性和环境因素的混合。全基因组关联研究已经阐明了AD的遗传基础，发现了与中枢神经系统固有免疫细胞-小胶质细胞的结构和功能相关的常见但风险较低的基因变化。而AD的环境驱动因素包括年龄、感染、饮食和污染物暴露。在AD中，小胶质细胞的变化以及斑块和缠结的发展在症状出现之前就发生了，可能源于改变大脑细胞生物学的环境因素的作用。因此，该项目旨在确定环境因素如何潜在地启动或影响小胶质细胞的分化，从而改变个人患阿尔茨海默病的机会。为了模拟这些影响，我们将使用一个体外人类衍生的3D脑器官模型，与暴露在不同环境因素下的小胶质细胞整合在一起，创造一个复杂的环境，模拟大脑内AD背景下发生的潜在结构和功能差异。一旦建立了这个模型，我们将使用AD来源的人类细胞系来进一步探索遗传易感性与环境之间的关系。该项目将共同提供关于遗传-环境关系如何改变个人患阿尔茨海默病的机会的信息，可能导致新的公共卫生指导和立法。

Alzheimer's Disease (AD) is a chronic neurodegenerative disease characterised by abnormal protein accumulation in the form of beta-amyloid plaques and tau tangles. Most cases of AD are sporadic and have a multifactorial basis, manifesting from a mix of genetic predisposition and environmental factors. Genome wide association studies have mapped out the genetic basis of AD identifying common, but low risk changes in genes associated with the structure and function of the innate immune cells of the central nervous system, the microglia. Whereas environmental drivers of AD include age, infection, diet, and pollutant exposure. In AD, changes to the microglia and the development of plaques and tangles occur prior to symptom onset and possibly originate from the actions of environmental factors altering the cell biology of the brain. Thus, this project sets out to establish how environmental factors potentially prime or affect the differentiation of the microglia, altering the chance of an individual developing AD. To model these effects, we will use an in vitro human-derived 3D brain organoid model integrated with microglia exposed to differing environmental factors, creating a complex environment that mimics potential structural and functional differences that occur in the context of AD within the brain. Once this model has been established, we will use AD-derived human cell lines to further explore the relationship between genetic predisposition and the environment. Together this project will provide information on how the genetic-environment relationship alters an individual's chance of developing AD, potentially leading to new public health guidance and legislation.