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)，不同基因的突变是 在不同的家族子集中的因果关系。除了遗传上的这种遗传异质性 病例中，大多数人表现出这些疾病的零星形式，其中有 没有已知的原因突变。部分由于这种零星的发病，人们普遍认为 (很大程度上不为人所知)环境力量在每一种环境的启动和/或发展中起着作用 上述障碍中的一种。这项提案将在果蝇中使用系统方法来识别 驱动启动的作用力，以及可能调制的常见细胞反应 进步。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。这些因素的影响 操作将通过以下7种不同的神经退行性表型和 生物标志物，包括一种新的内源性逆转录病毒复制分析。第二，我们将使用 一种相对较新的方法来净化受影响最严重的细胞群体，并分析 细胞核内活跃的转录。这项实验将识别常见的下游细胞 回应。最后，我们利用果蝇的高通量遗传方法来 对识别出的基因靶点的功能影响进行系统测试。

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.