An interdisciplinary approach to unravel mechanistic understanding of Frontotemporal lobar degeneration

揭示额颞叶变性机制理解的跨学科方法

• 批准号: 1916530
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1916530
• 关键词: interdisciplinary; approach; unravel; mechanistic; understanding

Dementia causes enormous personal hardship and costs the UK ~£23 billion every year. The second most common form is Frontotemporal lobar degeneration (FTLD). About 40% of FTLD cases have genetic causes, with >8% involving abnormal intronic GGGGCC hexanucleotide repeat expansions in the C9orf72 gene which can additionally cause motor neuron disease (OMIM #105550). These pathological expansions are actively transcribed and, via bidirectional repeat-associated non-ATG (RAN) translation, generate 5 different aggregate-forming GA, GR, PR, GP and AP dipeptide repeat proteins (DPRs).This project will gain new understanding of this type of FTLD by unravelling neurodegenerative pathomechanisms of DRPs through using interdisciplinary approaches. We will focus on the hypothesis that toxicity is caused by DRP structure, comparable to amyloid plaques in Alzheimer's disease. The project will capitalise on the complementary expertises of the three supervisors, and a readily available, unique set of 4 GFP-tagged constructs with high, pathologically relevant repeat numbers. The detailed aims and outcomes are:To generate purified DRPs and perform biochemical and biophysical analyses, in order to understand the reasons for their toxicity and identify useful therapeutic strategies which will benefit patients and their families.To generate transgenic Drosophila fly stocks to obtain primary neurons expressing the four DRPs. We will use powerful fly genetics and well established cell biological approaches to identify the neuronal death pathway and of the DRP-induced pathomechanisms upstream.There is substantial proof-of-principle for the use and translational potential of Drosophila To validate identified DRP pathomechanisms in mammalian contexts, we will carry out complementary experiments using well established DRP models in SH-SY5Y cells and inducible neuronal cell lines.This project is highly interdisciplinary, with the analysis of the dipeptide repeat proteins spanning systems from in vitro solvents to human and fly cell lines. The student will receive a broad training in characterisation of polypeptide structure and aggregation, cell culture, fly and human genetics, and cell biology, all in the context of genetic disease and neurodegeneration.

痴呆症造成了巨大的个人困难，每年花费英国约230亿英镑。第二种最常见的形式是额颞叶变性（FTLD）。约40%的FTLD病例有遗传原因，其中约8%涉及C9orf72基因中异常内含子GGGGCC六核苷酸重复扩增，这可能额外导致运动神经元疾病（omim# 105550）。这些病理扩增被积极转录，并通过双向重复相关的非atg （RAN）翻译，产生5种不同的聚集形成的GA、GR、PR、GP和AP二肽重复蛋白（DPRs）。本项目将通过跨学科的方法揭示DRPs的神经退行性病理机制，从而对这种类型的FTLD有新的认识。我们将重点关注毒性是由DRP结构引起的假设，类似于阿尔茨海默病中的淀粉样斑块。该项目将利用三位主管的互补专业知识，以及一套现成的、独特的4个gfp标记的结构，具有高的、病理相关的重复数。详细的目标和结果是：产生纯化的DRPs并进行生化和生物物理分析，以了解其毒性的原因并确定有用的治疗策略，这将使患者及其家人受益。目的：制备转基因果蝇种群，获得表达这四种DRPs的原代神经元。我们将使用强大的苍蝇遗传学和完善的细胞生物学方法来识别神经元死亡途径和drp诱导的上游病理机制。为了验证已确定的DRP在哺乳动物环境中的病理机制，我们将在SH-SY5Y细胞和可诱导的神经细胞系中使用已建立的DRP模型进行补充实验。该项目是高度跨学科的，分析了从体外溶剂到人类和苍蝇细胞系的跨系统的二肽重复蛋白。学生将接受多肽结构和聚集特征、细胞培养、苍蝇和人类遗传学以及细胞生物学等方面的广泛培训，所有这些都是在遗传疾病和神经变性的背景下进行的。