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功能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NIA阿尔茨海默病研究峰会2012：治疗和预防的路径导致了我们正在回应的RFA，提出了一些建议，推动了拟议研究中采用的战略。我们的建议汇集了一支非常强大和独特的多学科团队，拥有实现我们总体目标所需的相关技能。在目标1中，我们采用系统生物学的方法来挖掘一组真正独特的深层临床、临床、病理、基因组、表观基因组和转录组数据，这些数据来自两项关于衰老和痴呆的队列研究--宗教秩序研究和记忆与老龄化项目--的1000名受试者的冰冻背侧前额叶皮质脑组织，并与其他公开可用的功能数据集相结合。这些独特的数据为识别和提名药物发现的分子靶标提供了极好的底物。目标发现与灵活的翻译策略相结合，首先通过对同一区域的脑组织和目标2中的受试者进行有针对性的蛋白质组学研究来验证目标。在目标3中，在培养的人类神经元和星形胶质细胞中并行执行RNA干扰(RNAi)和过表达功能验证研究。最后，在目标4中，这些数据结合在一起，对最有希望的目标上的诱导多能干细胞(IPSC)来源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现实：它反映了以实用的心态部署尖端方法，其中仔细考虑了裁员，以降低风险并确保数据、网络模型和先导化合物的交付。这项拟议的研究将发现和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性，为新的临床试验奠定基础。 以及预防和治疗阿尔茨海默病的新方法。

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.