Functional Genomic Dissection of Alzheimer's Disease in Humans and Drosophila Models

总结 阿尔茨海默病（AD）预计到2050年将影响美国1300万人， 可治愈也不可预防。在最近的显著进展之后，AD和相关疾病的基因组结构 痴呆症（ADRD）正在成为人们关注的焦点。与其他常见和遗传复杂的疾病相似，AD是 其特征在于显著的基因座异质性和多基因易感性：风险或保护等位基因， 在许多不同的基因中，以及在大多数个体中，常见和罕见变异的子集可能 相互作用引发神经退化接下来的关键步骤包括确认负责基因， 了解疾病相关变异的功能影响，相关细胞类型的阐述， 途径，并确定多基因相互作用如何介导疾病风险。我们提出了一个综合 加速AD功能基因组学的计算和分层实验验证策略， 从AD测序项目（ADSP）的进步，并利用强大的技术，在水果 果蝇Drosophila melanogaster首先（AIM 1），利用为临床基因组开发的基础设施 资源和ENCODE项目，我们将把ADSP结果与其他人类数据，包括大脑， 转录组和表观基因组谱，优先考虑基因和变异的实验跟进。下一步（AIM 2）， 利用高通量果蝇筛选，我们将系统地操作2,000个保守的候选AD， 体内基因，以查明年龄依赖性神经退行性变的因果调节剂，包括与 Tau，Akt，和其他病理触发器。第三（AIM 3），对于200个优先候选基因的子集，我们将 生成定制的果蝇品系，并表征细胞类型表达和功能丧失表型。 最后（AIM 4），对于50个高优先级目标，我们将通过实验深入探索机制，包括测试 细胞类型的特定要求（神经元与神经胶质），并检查基因-基因相互作用， 途径。我们将与研究界广泛分享所有项目数据和资源（AIM 5）。我们 整合的、分层的、跨物种的策略有望使用强大的、 在果蝇的老化神经系统中进行体内测定，并且非常适合于在以下方面的相互交叉验证： 补充哺乳动物临床前模型。规模和时间范围目前在其他模型中不可能实现 系统，我们的创新实验策略将超越人类基因翻译的障碍， 发现和催化我们对AD病理生物学的理解的突破。

SUMMARY Alzheimer’s Disease (AD) is projected to affect 13 million people in the US by 2050 and remains neither curable nor preventable. Following remarkable recent progress, the genomic architecture of AD and related dementias (ADRD) is coming into focus. Similar to other common and genetically complex disorders, AD is characterized by substantial locus heterogeneity and polygenic susceptibility: risk or protective alleles are being identified in many distinct genes, and in most individuals, a subset of common and rare variants likely interact to trigger neurodegeneration. The critical next steps include confirmation of the responsible genes, understanding the functional impact of disease-associated variants, elaboration of the relevant cell types and pathways, and determining how polygenic interactions mediate disease risk. We propose an integrated computational and tiered experimental validation strategy to accelerate AD functional genomics, building on advances from the AD Sequencing Project (ADSP) and leveraging powerful technologies available in the fruit fly, Drosophila melanogaster. First (AIM 1), leveraging infrastructure developed for the Clinical Genome Resource and ENCODE projects, we will integrate ADSP results with other human data, including brain transcriptome and epigenome profiles, prioritizing genes and variants for experimental follow-up. Next (AIM 2), using high-throughput Drosophila screening, we will systematically manipulate 2,000 conserved, candidate AD genes in vivo to pinpoint causal modulators of age-dependent neurodegeneration, including interactions with Tau, Aß, and other pathologic triggers. Third (AIM 3), for a subset of 200 prioritized gene candidates, we will generate customized Drosophila strains and characterize cell-type expression and loss-of-function phenotypes. Lastly (AIM 4), for 50 high-priority targets, we will experimentally probe mechanisms in-depth, including testing of cell-type specific requirements (neurons vs. glia) and examining gene-gene interactions that define relevant pathways. We will broadly share all project data and resources with the research community (AIM 5). Our integrative, tiered, cross-species strategy promises rapid functional annotation of ADSP targets using powerful, in vivo assays in the aging nervous system of Drosophila, and is ideally suited for reciprocal cross-validation in complementary mammalian preclinical models. On a scale and timeframe not currently possible in other model systems, our innovative experimental strategy will transcend barriers to translation of human genetic discoveries and catalyze breakthroughs in our understanding AD pathobiology.