Traumatization of neurospheres for elicitation of tau aggregation in their constituent neurons

治疗阿尔茨海默病(AD)、慢性创伤性脑病(CTE)和额颞部痴呆(FTD)等神经退行性疾病是国家的当务之急。然而，目前还没有针对这些疾病的已知疗法。由于缺乏可靠的筛选工具来评估候选药物的表现，在临床试验中在人类患者身上进行测试之前，这一类别的药物发现一直受到阻碍。具体地说，制药业用来筛选候选药物的模型系统不能准确地概括退化人脑的微环境。为此，我们在不列颠哥伦比亚大学的研究小组与干细胞技术公司的科学家合作，提议应用组织工程的原理和方法来构建忠实和准确地模拟退化的人脑，用作药物筛选平台。具体地说，目前的提案寻求开发和验证构建模型器官的关键步骤-在其他健康的脑组织中引发神经变性，我们将利用对AD、CTE和FTD之间生化异同的最新见解来实现我们的目标。我们预计，目前的项目将为最终开发有机类生物制造平台奠定基础，该平台将整合到制药业现有的药物发现基础设施中。

The treatment of neurodegenerative diseases such as Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and frontotemporal dementia (FTD) is an urgent national priority. However, there are no known therapies against these diseases. Drug discovery in this category has been stymied by the absence of reliable screening tools for evaluating the performance of drug candidates before they are tested on human patients in clinical trials. Specifically, the model systems employed by the pharmaceutical industry to screen drug candidates do not accurately recapitulate the microenvironment of a degenerated human brain. To this end, our research group at the University of British Columbia, in collaboration with scientists from STEMCELL Technologies Inc., proposes to apply principles and methodologies of tissue engineering to construct a faithful and accurate mimic a degenerated human brain for use as a drug screening platform. Specifically, the current proposal seeks to develop and validate a key step in the construction of the model organ - the elicitation of neurodegeneration in otherwise healthy brain tissue, and we will employ recent insights about biochemical similarities and dissimilarities between AD, CTE and FTD to achieve our goal. We anticipate that the current project will lay the foundations for the eventual development of an organoid biomanufacturing platform that will be integrated into the pharmaceutical industry's existing drug discovery infrastructure.