Summary

 The goal of the project is to identify human-relevant genes that underlie an individuals’ risk to develop Alzheimer’s-related sleep problems and test those as interventions to restore sleep. Sleep dysfunction often precedes the emergence of cognitive deficits in AD and has a strong genetic basis. In aim 1, I will assess sleep behavior in a population of genetically diverse AD mice as they age, followed by genetic mapping analysis to identify genes involved in disordered sleep. In aim 2, I will use genome editing to test for a causal link between candidate gene expression on sleep duration and quality, and the onset and progression of memory deficits. These analyses will yield novel targets for therapeutic interventions to promote healthy sleep and delay or prevent dementia.

Project Details

The current proposal will be the first to identify novel genetic factors regulating disordered sleep by using a translationally relevant model system that incorporates genetic diversity into a model of AD. I will leverage MPRA and CRISPR-based screening tools to identify genomic variants associated with sleep disorder and their gene targets in vitro. A major innovation of the proposal is the use of bioinformatics tools to prioritize identified candidates by their relevance to humans. Candidate genes will be targeted to test whether they delay AD progression in vivo by improving sleep. The proposed work will identify translational gene targets that will alleviate sleep problems associated with aging and Alzheimer’s disease. Additionally, we will assess whether novel gene targets discovered here are also potent targets to reduce Alzheimer’s disease-related cognitive decline. Success will lead to improved understanding of the genetic contribution of sleep loss to onset of dementia. Ultimately, our objective is to identify gene candidates or gene pathways that can be further investigated as therapeutic targets for Alzheimer’s disease related sleep loss.