Pathway discovery, validation and compound identification for Alzheimer's disease

描述（由申请人提供）：拟议研究的总体目标是发现和临床前验证与导致认知能力下降的分子过程相关的新靶点，这是大多数AD试验的主要结果。最近的2012年NIA阿尔茨海默病研究峰会：治疗和预防之路，导致了我们正在回应的RFA，提出了一些建议，这些建议推动了拟议研究中采用的策略。我们的提案汇集了一个非常强大和独特的多学科团队，他们拥有实现我们总体目标所需的相关技能。在Aim 1中，我们采用系统生物学方法挖掘一套真正独特的深层临床、临床旁、病理、基因组、表观基因组和转录组数据，这些数据来自两项衰老和痴呆队列研究（宗教秩序研究和记忆与衰老项目）中1000名受试者的冷冻背外侧前额叶皮层脑组织，并结合其他公开可用的功能数据集。这些独特的数据为药物发现分子靶点的鉴定和提名提供了良好的基础。靶标发现与灵活的翻译策略相结合，该策略首先通过在Aim 2中对来自同一区域和受试者的脑组织进行靶向蛋白质组学研究来验证靶标。在Aim 3中，在培养的人类神经元和星形胶质细胞中并行进行RNA干扰（RNAi）和过表达功能验证研究。最后，这些数据汇集在Aim 4中，在最有希望的靶标上对诱导多能干细胞（iPSC）衍生的神经元和星形胶质细胞进行高通量小分子筛选。我们的提议雄心勃勃，但也切合实际：它反映了采用尖端方法的实际心态，其中仔细考虑了冗余，以降低风险，并确保数据、网络模型和先导化合物的交付。该研究将发现并验证与导致认知能力下降的分子过程相关的新靶点，并将证明一个或多个靶点的可药物性，为新的临床试验奠定基础

DESCRIPTION (provided by applicant): The overall goal of the proposed study is the discovery and preclinical validation of novel targets associated with molecular processes that lead to cognitive decline, the primary outcome of most AD trials. The recent NIA Alzheimer's Disease Research Summit 2012: Path to Treatment and Prevention that led to the RFA to which we are responding, made a number of recommendations which motivated the strategy adopted in the proposed study. Our proposal brings together an exceptionally strong and unique multi-disciplinary team with the relevant skills needed to achieve our overall goal. In Aim 1, we take a systems biology approach to mine a truly unique set of deep clinical, paraclinical, pathologic, genomic, epigenomic, and transcriptomic data assembled from frozen dorsolateral prefrontal cortex brain tissue of 1000 subjects from two cohort studies of aging and dementia, the Religious Order Study and the Memory and Aging Project, in conjunction with other publicly available functional datasets. These unique data provide an excellent substrate for the identification and nomination of molecular targets for drug discovery. Target discovery is coupled with a flexible translational strategy that first validates targets by a targeted proteomic study of brain tissue from the same region and subjects in Aim 2. In Aim 3, an RNA interference (RNAi) and overexpression functional validation study in cultured human neurons and astrocytes is executed in parallel in Aim 3. Finally, these data come together in Aim 4 which performs high throughput small molecule screens on neurons and astrocytes derived from induced pluripotent stem cells (iPSC) on the most promising targets. Our proposal is ambitious but realistic: it reflects the deployment of cutting-edge approaches with a practical mindset in which redundancies have been carefully considered to mitigate risk and ensure the delivery of data, network models and lead compounds. The proposed study will discover and validate novel targets associated with molecular processes that lead to cognitive decline, and it will demonstrate the druggability of one or more targets, setting the stage for clinical trials with new and novel approaches to the prevention and treatment of AD.