Novel high-throughput approaches for the rapid analysis of target engagement by mass spectrometry

通过质谱快速分析目标参与的新颖高通量方法

• 批准号: 2434814
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2434814
• 关键词: Novel; throughput; approaches; rapid; analysis

Alzheimer's disease (AD) is one of the most common form of neurodegenerative diseases known today, affecting approximately 50 million people worldwide. The pathogenic mechanism is characterised by the formation of toxic A-beta oligomeric species and aggregates that disrupt neuronal function. One of the neuronal cell types most affected by A-beta are glutamatergic neurons, which are required to receive and transmit sensory signals. For example, loss of the sense of smell (olfactory dysfunction) is one of the earliest symptoms of AD in humans. Similarly, in C. elegans, chemosensory deficits in behaviour mediated via glutamatergic neurons, occurs in already young animals expressing A-beta in the nervous system. We however do not know which glutamatergic neuronal subtype loses its signalling activity first as a consequence of A-beta-associated toxicity during AD progression and how neuronal function can be protected.This project will determine which neuronal circuit succumbs first to A-beta expression during AD progression and how Hsp90 protects glutamatergic neuronal function. Therefore, we will establish an improved C. elegans model of A-beta-associated Alzheimer's Disease (AD) that allows to monitor neuronal signalling activity throughout aging and progression of the disease; using a calcium reporter in combination with a glutamate sensor. The reporter would allow to determine when neuronal signalling activity declines, which neuronal subtypes are affected first and whether protective molecules (such as chaperones and pharmacological compounds) safeguard neuronal signalling activity. Identification of the exact neuronal subtype affected by A-beta expression and how Hsp90 preserves signalling function will provide novel insights into how AD develops. This will facilitate the development of new treatment options that can be applied early in the disease process to delay or even prevent further progression of the disease. The improved C. elegans AD reporter will replace mouse neurodegenerative disease models such as AD, to investigate the protective effects of chaperones and pharmacological compounds at the level of neuronal signalling activity and correlated to behavioural output.

阿尔茨海默病（AD）是当今已知的最常见的神经退行性疾病之一，影响全世界约5000万人。致病机制的特征在于形成破坏神经元功能的毒性A-β寡聚物和聚集体。受A-β影响最大的神经元细胞类型之一是神经元能神经元，其需要接收和传递感觉信号。例如，嗅觉丧失（嗅觉功能障碍）是人类AD的最早症状之一。同样，在C.在线虫中，通过神经元介导的行为中的化学感觉缺陷发生在已经在神经系统中表达A-β的年幼动物中。然而，我们不知道在AD进展过程中，哪一种β-淀粉样蛋白能神经元亚型首先失去其信号传导活性，以及如何保护神经元功能。本项目将确定在AD进展过程中，哪一种神经元回路首先屈服于β-淀粉样蛋白表达，以及Hsp 90如何保护β-淀粉样蛋白能神经元功能。因此，我们将建立一个改进的C。A-β相关的阿尔茨海默病（AD）的elegans模型，其允许在整个衰老和疾病进展中监测神经元信号传导活性;使用钙报告基因与谷氨酸传感器的组合。报告基因将允许确定神经元信号传导活性何时下降，哪些神经元亚型首先受到影响，以及保护性分子（例如分子伴侣和药理学化合物）是否保护神经元信号传导活性。确定受A-β表达影响的确切神经元亚型以及Hsp 90如何保留信号传导功能将为AD的发展提供新的见解。这将有助于开发新的治疗方案，可以在疾病过程的早期应用，以延迟甚至防止疾病的进一步进展。改良的C. elegans AD报告基因将取代小鼠神经退行性疾病模型，如AD，以研究伴侣蛋白和药理学化合物在神经元信号传导活性水平上的保护作用，并与行为输出相关。