Pathway Discovery, Validation and Compound Identification for Alzheimer's Disease
EMSL Project ID
51619
Abstract
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. First, 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. Drug 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. We plan to measure protein abundances of the nominated targets across ~1000 of both aforementioned cohorts. Correlation of protein abundance with cognitive decline or other pathological signs (e.g. neurofibrillary tangles and amyloid plaques) will suggest a valid link between the protein and Alzheimer’s disease. Proteins validated with targeted protein will be passed to further validation steps. In addition, an RNA interference (RNAi) and overexpression functional validation study in cultured human neurons and astrocytes is executed in parallel. Finally, these data come together in a stage 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.
Project Details
Start Date
2020-10-01
End Date
2023-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members