Dynamical signaling and gene regulation in stress and aging

University Of California, San Diego, La Jolla CA

Investigators

Abstract

Project Summary Cells respond to intracellular and extracellular challenges through intricate signaling pathways. An increasing number of studies revealed that the temporal dynamics of signaling pathways play crucial roles in controlling cellular processes. However, the basic mechanisms underlying the regulation and function of signaling dynamics remain largely unclear. Protein kinase A (PKA) is a highly conserved prototypic kinase that regulates many cellular behaviors, such as cell growth and stress resistance, through gene expression programs. Under physiological conditions, PKA displays various temporal dynamics of signaling activity. Defects in dynamic regulation of PKA activity can lead to disastrous diseases, such as neurodegeneration, cancer and heart disease. For over a decade, the research in our lab has been focused on understanding the regulation and function of PKA signaling dynamics upon stress. In this renewal, we propose to expand our research to study the mechanisms underlying dynamical regulation of PKA signaling in cellular aging and deterioration using budding yeast as a model system. Our preliminary results showed that PKA activity decreased in a fraction of aging cells and the interactions between PKA and the heme-activated protein (HAP) complex may drive this divergence of signaling dynamics among aging cells. Building upon these results, we will combine computational modeling with quantitative experiments to interrogate the regulatory circuit that drives the age- induced dynamic changes in PKA signaling. Specifically, in Aim 1, we will perturb the PKA-HAP circuit and evaluate the effects on PKA dynamics and their roles in regulating aging and lifespan. In Aim 2, we will evaluate the contributions of PKA dynamics to gene expression changes during aging. In Aim 3, we will investigate how PKA controls messenger ribonucleoprotein granules, e.g. processing bodies (P-bodies), to influence the posttranscriptional regulation of gene expression in aging. The completion of this project will further our basic understanding about the general mechanisms of PKA signaling in aging from a network perspective and will illuminate molecular causes of age-related diseases, setting the stage for new therapeutic strategies against them.