Current Research Interests
Integrating large datasets to uncover novel genes relevant to human health
We are living in an exciting time where there exists many high-throughput methods to collect massive amounts of high-dimensional biological data (e.g., genome, transcriptome, metabolome, phenome, et cetera) from which we can use established statistical methods to predict new molecules relevant to human disease. The current pressing problem though, lies in how we can take the next step with these large datasets and integrate them to uncover new associations and interactions previously masked in these datasets by the “simplistic” approach of studying each individually.
To try to understand how to integrate data from different realms of biology, I have been using a model, the nematode Caenorhabditis elegans. Very recently new resources and tools have been developed for this model to make it the perfect test-case for data integration, these include a deep-sequenced multi-mutant library (Thompson et al., 2013) and an automated computer vision phenotyping system that can assay greater than 20 phenotypes of ~ 100 worms simultaneously (Swierczek et al, 2011). I want to know how we can best integrate these datasets, comparing multivariate regression-type approaches with unsupervised learning approaches. Although my work has primarily utilized C. elegans, I am excited by the prospect of working in collaboration with clinical, epidemiological and genomics research groups on similar datasets in other species, as the same statistical methodologies would apply.
Ciliated sensory neuron development and function
An intriguing finding from my Ph.D. research was that age-dependent changes in sensory signalling altered learning (Timbers et al., 2013). Thus, I subsequently sought to develop my understanding of sensory systems by carrying out my postdoctoral research at Simon Fraser University (Burnaby, BC) in the lab of Dr. Michel Leroux because he is a world-leading expert in the underlying mechanisms of the development and function cilia.
Cilia are important organelles that emit from the cell membrane of almost all eukaryotic cell types and are required for virtually all sensory processes, including olfaction, mechanosensation, photosensation and thermosensation, as well as function in modulating various core signaling pathways (Wnt, Hegdehog, PDGF) important for development. Dysfunction of cilia is implicated in a number of human diseases, including polycystic kidney disease, congenital heart disease, and an emerging group of genetic disorders termed ciliopathies (e.g., Bardet-Biedl, Meckel-Gruber and Joubert Syndromes). In these ciliopathies, collective disruption of many, if not all, cilia in the human body results in a plethora of defects, including retinal degeneration, organ cyst formation, obesity, brain malformations, and various other ailments (Baker & Beales, 2009). Here I have been performing high-throughput, large-scale genetic screens and statistical genetic analysis in C. elegans to uncover new genes critical for ciliated sensory neuron development and function.
###Molecular mechanisms of learning and memory
My graduate research with Dr. Catharine Rankin at the University of British Columbia (Vancouver, BC) uncovered novel molecular mechanisms governing learning and memory through genetic and behavioural studies of a form of non-associative learning, mechanosensory habituation, in C. elegans. This work, which led to four publications as well as an additional manuscript currently under review at PNAS, (1) revealed that the transcription factor CREB is required for long-term habituation, and localized its function to two identified interneurons (Timbers & Rankin, 2011; Li & Timbers et al., 2013), (2) genetically dissected intermediate- and long-term memory and demonstrated that these memories are formed by differentially altering the synaptic machinery (Li & Timbers et al., 2013), (3) paired an automated behavioural tracking system, the Multi-worm tracker (Swierczek et al., 2011), with optogenetics to uncover that age-related changes in sensory transduction begin in middle-age and lead to learning deficits (Timbers et al., 2013), and (4) uncovered a novel role for O-GlcNAcylation post-translational modification in learning (Timbers et al., under Review at PNAS).