Grant: CIHR Fellowship

Aging is a risk factor for many diseases, including neurodegenerative, cardiovascular diseases, and cancers. One hallmark of aging organisms is the accumulation of molecular damage, which in turn activates protective stress responses that mitigate cellular damage. Activating and controlling stress responses is an effective way to promote healthy aging. Therefore, understanding the genetic and molecular composition of stress response pathways is a promising path toward novel therapies for age-related disorders and to promote healthy aging. The genetically simple model organism C. elegans (worm) is an excellent system for studying mechanisms that underlie healthy aging. The C. elegans Nuclear Hormone Receptor NHR-49 is a transcription factor that is required for stress response activation. Loss of NHR-49 reduces life and health span, and stress resistance in animals. However, the genetic and molecular pathways through which NHR-49 promotes healthy aging are poorly characterized. A reverse genetic screen identified 3 kinases whose genetic loss of function mimics nhr-49 loss. These kinases are predicted to target NHR-49 and have human orthologs associated with age-related diseases. I will test whether these kinases regulate NHR-49 to promote healthy aging. Critically, the NHR-49 homolog, peroxisome proliferator-activated receptor alpha (PPARa), regulates aging-associated molecular processes; this suggests that studying NHR-49 can unveil information pertinent to studying human aging. Using cutting-edge biochemical, genetic and genomic approaches, I will disentangle the molecular pathway of NHR-49/PPARa regulation and reveal new insights into potential interventions for age-associated diseases.