A systems approach to uncover upstream activators and common downstream pathways of neurodegeneration in a Drosophila model

项目摘要 大多数神经退行性疾病表现出高度异质性的遗传基础。为 例如，阿尔茨海默病（AD）、肌萎缩侧索硬化症（ALS）、额颞叶 脑叶变性（FTLD）和帕金森病（PD），不同基因的突变， 在不同的家庭子集中是因果的。除了这种遗传异质性， 在某些情况下，大多数个体表现出这些疾病的散发形式，其中 没有已知的致病突变部分由于这种零星发作，人们普遍认为， （很大程度上未知）环境力量在每一个的启动和/或进展中起作用。 上述疾病。这项建议将使用系统的方法在果蝇，以确定 驱动启动的力量，以及可能调节 进展这将通过三个科学目标来实现。首先，我们将测试一系列 细胞应激源、行为应激源和损伤/炎症模型。成效为何 将通过以下7种不同的神经退行性表型来测定操作， 生物标志物，包括内源性逆转录病毒复制的新测定。第二，我们将使用 一种相对较新的方法来纯化受影响最大的细胞群， 在细胞核内活跃的转录。本实验将确定常见的下游细胞 应答最后，我们利用果蝇的高通量遗传方法， 系统地测试所鉴定的基因靶标的功能影响。

PROJECT ABSTRACT Most neurodegenerative disorders exhibit highly heterogeneous genetic underpinnings. For example, with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and Parkinson's disease (PD), mutations in different genes are causal in distinct subsets of families. In addition to this genetic heterogeneity among inherited cases, the majority of individuals exhibit sporadic forms of these disorders in which there are no known causal mutations. In part because of this sporadic onset, it is widely accepted that (largely unknown) environmental forces are at play in the initiation and/or progression of each of the above disorders. This proposal will use a systems approach in Drosophila to identify forces that drive initiation, as well as common cellular responses that may modulate progression. This will be accomplished by three scientific aims. First, we will test a series of cellular stressors, behavioral stressors, and models of injury/inflammation. The effects of these manipulations will be assayed by following 7 different neurodegenerative phenotypes and biomarkers, including a novel assay of endogenous retrovirus replication. Second, we will use a relatively new approach to purify the population of cells that are most impacted, and profile active transcription within the nuclei. This experiment will identify common downstream cellular responses. Finally, we take advantage of high throughput genetic approaches in Drosophila to systematically test for functional impact of identified gene targets.