Thursday, March 13, 2025
3/13/2025
Project Summary The functional significance of actin in cellular health and fitness is unquestionable, as the actin cytoskeleton is required for a diverse array of cellular processes as simple as movement and motility. The loss of function of actin is seen in clinical manifestations in many diseases, and specifically during the aging process. However, these studies are limited to the cytoplasm, despite actin being identified in the nucleus over 50 years ago. The lack of studies of nuclear actin during aging is likely owning to the poorly understood mechanistic function and the available tools to study nuclear actin. In fact, even studies of cytoplasmic actin during aging is still a burgeoning field, making the studies of nuclear actin even more elusive. This highly innovative proposal aims to tackle this major black hole in the field, leveraging our expertise in cytoplasmic actin to shift our research direction into studying nuclear actin in DNA repair and transcriptional regulation. Our first goal is to synthesize a robust method to visualize the quality, function, and dynamics of nuclear actin during stress and aging in C. elegans. As a new field, there are still no existing tools to reliably study nuclear actin in perhaps the most powerful genetic model organism for aging research. Therefore, we propose to synthesize multiple methods to reliably stain the numerous variants of nuclear actin. Furthermore, we will leverage diverse genetic methods to directly study how changes to nuclear actin stability, function, and dynamics can impact the aging process. We hypothesize that nuclear actin dysfunction during aging contributes to physiological consequences and perturbing nuclear actin can result in premature aging. Emerging studies have implicated nuclear actin in DNA and RNA regulation, quality control, and function, which is unsurprising considering the contents of the nucleus. Here, we aim to study the hypothesis that nuclear actin can influence DNA repair. Specifically, we hypothesize that nuclear actin filaments form under stress to recruit DNA repair machinery, and breakdown of this process is what leads to genomic instability and decline of organismal health during aging. As an alternative hypothesis, we also propose that nuclear actin may play an important role in transcriptional fidelity. Like DNA integrity, transcriptional fidelity is important to prevent the synthesis of mutated proteins that can aggregate and cause physiological consequences during aging. Thus, we argue that nuclear actin can drive protein homeostasis by preventing transcriptional errors, and the breakdown of this functional process during aging can result in age-related disease. Ultimately, we propose to venture into two new research directions for our lab: nuclear actin and DNA repair. Moreover, we propose to merge these two novel fields into a highly innovative study understanding how nuclear actin impacts transcriptional fidelity and vice versa, creating a unique research proposal perfectly in line with the vision of the Stephen I. Katz Early Stage Investigator Research Project Grant.
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