IDENTIFICATION OF GENERIC SUPRESSORS OF PROTEINOPATHIES

蛋白质病通用抑制剂的鉴定

• 批准号: MR/J006904/1
• 负责人: David Rubinsztein
• 金额: $ 51.91万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ006904%2F1
• 关键词: IDENTIFICATION; GENERIC; SUPRESSORS; PROTEINOPATHIES

We aim to identify genes that reduce the toxicity of a wide range of different mutant proteins that cause neurodegeneration. We will identify such genes and pathways by performing a bioinformatics analysis of existing genetic screens for modifiers in lower organisms (from yeast to Drosophila), as well as targeted studies in all systems, including high confidence genome wide association study hits for Alzheimer's and Parkinson's disease and ALS. Using multiple data sources, we will identifyhallmark features of "generic modifiers" and use computational methods to identifynew modifiers, which will then be tested for efficacy in fruit fly models of different diseases, like Huntington's disease and forms of dementia. Novel modifiers showing efficacy in morethan one disease will be studied in cell models and fruit flies to identify mechanisms ofaction. The identification of such "generic" supressors and their mechanisms wouldcreate a list of high priority targets for consideration for therapeutic development and/ordetailed mechanistic analyses, as these would be acting on a range of diseases and areexpected to affect core processes.

我们的目标是确定基因，减少毒性的各种不同的突变蛋白，导致神经变性。我们将通过对低等生物（从酵母到果蝇）中现有的修饰基因筛选进行生物信息学分析，以及在所有系统中进行有针对性的研究，包括阿尔茨海默氏症和帕金森氏症以及ALS的高置信度全基因组关联研究，来识别这些基因和途径。使用多个数据源，我们将识别“通用修饰剂”的标志性特征，并使用计算方法识别新的修饰剂，然后在不同疾病的果蝇模型中测试其功效，如亨廷顿病和痴呆症。将在细胞模型和果蝇中研究对多种疾病显示功效的新型修饰剂，以确定作用机制。这种“通用”抑制因子及其机制的确定将创建一个高度优先的目标清单，供治疗开发和/或详细的机制分析考虑，因为这些将作用于一系列疾病，并预计会影响核心过程。

项目成果

NeuroGeM, a knowledgebase of genetic modifiers in neurodegenerative diseases.

• DOI: 10.1186/1755-8794-6-52
• 发表时间: 2013-11-14
• 期刊: BMC medical genomics
• 影响因子: 2.7
• 作者: Na D;Rouf M;O'Kane CJ;Rubinsztein DC;Gsponer J
• 通讯作者: Gsponer J

Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.

• DOI: 10.1038/cdd.2014.151
• 发表时间: 2015-03
• 期刊: Cell death and differentiation
• 影响因子: 12.4

siRNA screen identifies QPCT as a druggable target for Huntington's disease.

siRNA 筛选将 QPCT 识别为亨廷顿病的药物靶点。

• DOI: 10.17863/cam.17368
• 发表时间: 2015
• 作者: Jimenez-Sanchez M

The Hedgehog signalling pathway regulates autophagy.

• DOI: 10.1038/ncomms2212
• 发表时间: 2012
• 期刊: Nature communications
• 影响因子: 16.6