Towards an Understanding of S100A9 Activation of TLR4: Incorporating a Biochemical and Evolutionary Perspective.
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Date
2024-12-19
Authors
Chisholm, Lauren
Journal Title
Journal ISSN
Volume Title
Publisher
University of Oregon
Abstract
The central puzzle of my dissertation work is understanding how two molecules with very different physiochemical properties activate the same receptor, Toll-like receptor 4 (TLR4). TLR4 is an innate immune receptor that responds to both the bacterial glycosylated phospholipid LPS and small soluble host proteins. Despite decades of work, we have little mechanistic understanding of how soluble proteins activate this receptor. S100A9 is one such soluble protein, or Damage Associated Molecular Pattern (DAMP), that activates inflammatory pathways via Toll-like receptor 4 (TLR4). This activity plays important homeostatic roles in tissue repair, but can also contribute to inflammatory diseases. The mechanism of activation is unknown. Learning more about the mechanism of S100A9-induced inflammation can improve our understanding of many disease pathologies, as well as providing a promising new therapeutic target. In this dissertation I describe my work addressing this gap in the literature, using biochemical, biophysical, computational, and evolutionary methods.
This dissertation includes previously published and unpublished co-
authored material.