Use of c. Elegans as a model to study aging-associated neurodegeneration - aging can cause neurodegeneration and is also a major risk factor for neurodegenerative diseases

Duke University received a $1,019,484.58 Project Grant award from the National Institutes of Health's National Institute on Aging under the Aging Research program (CFDA 93.866) for the period September 1, 2021 through May 31, 2022. The award will support research using the nematode C. elegans as a model organism to study aging-associated neurodegeneration at the molecular level, with the goals of uncovering novel mechanisms underlying this process and establishing C. elegans neurons as a powerful tool for further investigation. Specifically, the researchers will determine the function and regulation of antimicrobial peptides in aging-associated neurodegeneration and establish cell-autonomous mechanisms of neurodegeneration in aged animals. Completion of this research is expected to lead to new insights into the pathogenesis of neurodegenerative disorders associated with aging.

However, the molecular mechanisms underlying aging-­associated neurodegeneration are not well understood yet. Therefore, our-­long-­term goal is to understand the molecular mechanisms undying neurodegeneration in aging and neurodegenerative diseases. The objective of this proposal is to use c. Elegans as a model to uncover novel mechanisms underlying aging-­associated neurodegeneration. This proposal builds on our recent punished work, in which we revealed that antimicrobial peptide (amps) released by epidermal cells in aged animals lead to neurodegeneration through activating a neuropeptide receptor (NPR). Importantly, our collaborators showed that signaling via the same molecular players (amps and NPR) also leads to neurite degeneration in RAT cortical neurons, supporting the conclusion that the mechanisms identified in our system are preserved in mammalian neurons. Based on these exciting findings, we propose to use genetic and genomic methods to further examine the signals that cause the overexpression of amps in aged animals and to uncover the transcriptional regulators that lead to neurodegeneration upon aging. We believe that careful analysis of aging-­associated neurodegeneration in c. Elegans will reveal previously unknown but potentially conserved mechanisms that govern fundamental features of neurodegeneration in aging. This proposal will determine the function and regulation of amps in aging-­associated neurodegeneration (aim 1), and establish cell autonomous mechanisms underlying neurodegeneration in aged animals (aim 2). IT is expected that completion of this proposal will lead to the discovery of novel mechanisms of aging-­associated neurodegeneration, the establishment of c. Elegans PVD neurons as a powerful model to study aging associated neurodegeneration, and the generation of new tools for further studies. As many neurodegenerative disorders are associated with aging, our studies may lead to a better understanding of the pathogenesis of these diseases.