Aging involves the gradual decay of tissues, organs and organ systems. Early in this process, impermeability or selective permeability of tissues deteriorates and gives rise to increasing organ dysfunction. This phenomenon has been termed barrier dysfunction, yet the molecular mechanisms, which drive tissue ?leakiness? and contribute to organ aging are unclear. To interrogate the underlying mechanism, we examine the aging intestine of the nematode, C. elegans, to determine how resiliency of the intestinal barrier withstands the test of time. Preliminary screens from my lab have linked age regulation by the Heat Shock transcription Factor, HSF-1, with the activity of the intestine-specific actin protein, ACT-5. Although expressed in a small number of cells and comprising less than 2% of total worm actin, ACT-5 plays an essential role in intestinal and organismal aging. Through the proposed five-year research period, we aim to understand how age-related decline in HSF-1 activity contributes to tissue dysfunction and animal aging. In particular, we will characterize the molecular mechanism of age progression in which HSF-1 dysregulation impairs cellular architecture and intestinal physiology. We speculate that age-associated decline in HSF-1 activity impairs specialized actin networks in intestinal epithelium, which ultimately compromise vesicular traffic, cell-cell junctional integrity and tissue barrier maintenance. We have already identified the stress-activated JUN kinase, KGB-1, as a repressed transcriptional target of HSF-1, which catalyzes phosphate addition to the ACT-5 protein within its binding site for the actin filament stabilizing Troponin complex. Accumulation of phosphorylated ACT-5 at serine residue 232 dramatically influences the structural integrity of the apical terminal web and vesicular transport across it. Overall, the proposed research will uncover a phosphorylation-dependent actin relaxation mechanism under HSF-1 control, which facilitates vesicular transport across dense, actin-rich ?roadblocks? while still maintaining their structural rigidity and cellular architecture.
Aging involves the gradual decay of tissues, organs and organ systems, in which impermeability or selective permeability of tissues deteriorates and gives rise to increasing organ dysfunction. My laboratory has uncover a phosphorylation-dependent actin relaxation mechanism under control of the Heat Shock transcription Factor, HSF1, which facilitates vesicular transport across the dense, actin-rich terminal web of intestinal epithelia while still maintaining its structural rigidity and cellular architecture. Age-associated loss of HSF-1 activity causes the gradual decay of this system, which drives tissue barrier dysfunction and age progression.