Leveraging Hydroides elegans to Uncover NfKb Pathway Roles in Innate Immune Discrimination

About This Grant

PROJECT SUMMARY NF-κB is a central regulator of innate immune signaling, orchestrating processes like inflammation, cell survival, and tissue remodeling in response to microbial stimuli. Despite its essential role, the mechanisms by which NF-κB mediates beneficial responses (e.g., tissue homeostasis) versus pathological ones (e.g., chronic inflammation and cell death) remain unresolved. Dysregulation of NF-κB signaling is a hallmark of inflammatory bowel disease (IBD), where persistent inflammation damages the intestinal lining and leads to debilitating symptoms. Current treatments are often nonspecific and fail to address the underlying immune signaling misregulation. This project seeks to resolve how NF-κB achieves outcome specificity utilizing Hydroides elegans, a marine annelid with an innate-only immune system and a uniquely diverse set of NF-κB homologs. In Hydroides larvae, the bacterial toxin Mif1 elicits opposite outcomes in a dose-dependent manner (low concentrations induce morphogenesis, while high concentrations cause cytotoxicity). Using a novel RNAi platform developed by the candidate, the project will integrate spatial gene expression mapping (AIM 1), functional knockdowns (AIM 2), and downstream transcriptomic profiling (AIM 3) to elucidate how distinct NF- κB homologs mediate resilience or pathology in response to the same microbial input. The overarching hypothesis is that individual NF-κB homologs function within spatially distinct cellular domains and regulate both shared and unique transcriptional programs that determine the outcome of microbial challenge. By generating a systems-level model of NF-κB immune specificity, this proposal will directly inform strategies to selectively modulate NF-κB signaling, allowing for more targeted and effective IBD therapeutics. The proposed work will also provide rigorous training in host–microbe interactions and innate immunity, positioning me for a biomedical career at the interface of translational immunology and microbiology.