Elucidating Genetic Regulatory Networks in Alzheimer's Disease and Drug Repurposing

点击翻译按钮获取中文摘要

BackgroundAlzheimer's Disease (AD) is a progressive neurodegenerative disease and is the most prevalent form of dementia. Currently, there are no therapies that directly affect disease progression. Re-purposing established compounds is an attractive approach to developing proofs of principle for new strategies.AD progression occurs in a cell-type specific manner. Gene regulatory networks (GRNs) serve as a model linking cell-type specific regulatory elements to their targets. Regulators of gene expression are ideal targets for compounds because they control several genes that can become altered together in disease pathogenesis. This project will uncover mechanistic insights into AD as well as produce a reproducible and robust drug repurposing pipeline.AimsThe main objective is to build a robust pipeline that identifies cell-type specific GRNs affected by AD. Then, I will use these GRNs to identify potential disease-associated targets against which currently approved drugs are directed. Once identified in silico results can be validated using iPSC models established in the laboratory.MethodsPublic AD snRNA-seq datasets will be integrated to provide sufficient statistical power for new gene discovery after standardized pre-processing and QC. Systematic assessment of GRNs will be performed. Network stability, preservation and pathway significance will be assessed through statistical tests and down-sampling. In silico causal modeling approaches will be explored to assess the relative importance of genes within the sub-networks. Also, differences between AD and non-diseased control networks will be considered to prioritise disease-associated sub-networks. Drug compounds that potentially "reverse" dysregulation of sub-networks will be identified in silico using perturbation databases like ConnectivityMap. Initial validation of findings will be performed in vitro in iPSC models. Translational OpportunitiesThis project has the potential to identify and provide preliminary human validation of novel targets that could be assessed for therapeutic efficacy in AD based on drug repurposing.