IDENTIFICATION OF GENERIC SUPRESSORS OF PROTEINOPATHIES

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。新型修饰剂在一种以上的疾病中表现出功效，将在细胞模型和果蝇中进行研究，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。

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.