Elucidating the role of ER remodeling in aging of C. elegans

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT An aging human population has revealed the burden of chronic illness and age-related disease, and by understanding the genetic and environmental factors that drive aging, we will be better suited to develop and test therapeutics that slow age-related disease. As biological aging is influenced by both genetics and the environment, our laboratory studies the cellular and molecular drivers of aging, with a particular focus on inter- organelle communication in disease. Here, we newly describe a dramatic reorganization of endoplasmic reticulum (ER) subdomains in aging C. elegans. The ER mediates inter- and intracellular signaling through these sheet and tubule domains, and sheet:tubule balance is critical for cell function. ER tubules store calcium and lipids, and at specialized membrane contact sites, they regulate mitochondrial dynamics. We find that the aging ER undergoes a loss of rough ER sheets and expansion of smooth ER tubules, and our data suggest that modifying ER structure is sufficient to preserve mitochondrial morphology in age, making the ER a potential target in preventing age-related mitochondrial fragmentation. Though autophagy is seen as cytoprotective in aging, we show that autophagy is necessary for age-related ER remodeling. This may be explained by ER- phagy, a form of ER-selective autophagy that has not been studied in the context of aging, as ER-phagy shares common recycling processes. Finally, we demonstrate that caloric restriction, which extends lifespan, prevents this age-related loss of ER morphology. Therefore, we hypothesize that dysregulated ER-phagy drives age- related ER remodeling and that dietary restriction promotes longevity by mitigating this loss of ER form and function. To discern whether these changes are attributable to selective ER-phagy, rather than general autophagy, I will use a combination of in vivo imaging, fluorescent reporters, and RNAi to investigate the molecular mechanisms leading to a change in ER subdomains with age (Aim 1). In Aim 2, I will use dietary restriction, a robust longevity paradigm, to investigate the cause(s) and consequence(s) of ER remodeling in healthspan and lifespan regulation. This work will be conducted at Vanderbilt University under the supervision of Dr. Kristopher Burkewitz, Assistant Professor of Cell & Developmental Biology, who discovered roles for ER function in lifespan regulation through ER-mitochondrial crosstalk. I will additionally be supported by Dr. David Miller, Professor of Cell & Developmental Biology, whose lab is experienced in electron microscopy and pioneered many genetic engineering techniques I will perform in C. elegans. In these studies, I will receive feedback from a strong advisory committee with expertise including interorganelle signaling, membrane dynamics, and aging physiology. Successful completion of this project will not only advance our understanding of cell biology and the role of the ER in aging but also establish ER structure and function as therapeutic targets in the treatment of age-related disease.