UCLA

Physiological functioning of an organ system such as healthy brain functioning is enabled by orchestrated information flow between molecular entities within cells, between cells, and across tissues and its understanding requires a systems approach. In complex disease such as Alzheimer’s disease, there are numerous subtle, moderate, and strong perturbations across biological networks which result in disease onset and progression. High-throughput multi-omics profiling of genetic variants, the epigenome, transcriptome, proteome, metabolome, and microbiome is a first step in probing the complexity of biological systems and disease etiologies. There remains the problems of multi-omics integration, modeling and interpretation, and accessibility of computational analyses. To address these issues, in the methods development section of my dissertation research, I developed the complete overhaul of the web server for Mergeomics, a method for pathway- and network-level understanding of complex disease using multi-omics integration, which significantly improved the usability and functionality of the tool. To facilitate omics-driven drug discovery, I implemented the PharmOmics web server and the direct pipeline from Mergeomics, allowing users to gain immediate therapeutic insight from disease-associated pathways, key drivers, and key driver subnetworks. The second focus of my dissertation was the application of systems biology analytical tools to understand metabolic contributions to Alzheimer’s disease. I determined hippocampal and hypothalamic cell type specific alterations in response to amyloid-beta accumulation in the 5XFAD mouse model and investigated the effect of metabolically challenging 5XFAD mice with fructose overconsumption and supplementation with docosahexaenoic acid and nicotinamide riboside. I identified cell type- and tissue-resolved pathway and network mechanisms of disease exacerbation by metabolic challenge and disease alleviation by docosahexaenoic acid and nicotinamide. My efforts in developing the web server implementations of Mergeomics and PharmOmics have promoted greater accessibility of deriving mechanistic insight from big biological data for the broader scientific community, and use of these tools have allowed unbiased examination into the connection between metabolic syndrome and Alzheimer’s disease and uncovered potential therapeutic targets and strategies via dietary modulation.