<p dir="ltr">This thesis explores the intricate mechanisms governing paracellular permeability, a process vital for maintaining homeostasis and barrier integrity in epithelial and endothelial tissues. Central to this exploration are tight junctions (TJs), multi-protein complexes that regulate substance movement between cells. The thesis begins with a comprehensive literature review synthesizing current research on how bacterial and viral proteins can enhance paracellular permeability or modulate TJs, highlighting their significance in both scientific and medical fields.</p><p dir="ltr">A focal point of the thesis is the detailed study of the <i>Listeria</i> adhesion protein (LAP), an epithelial TJ modulator (TJM). LAP’s interaction with the epithelial receptor, Hsp60, facilitates the translocation of <i>Listeria monocytogenes </i>across the epithelial barrier, presenting a novel approach for drug delivery. Addressing the limitations of current TJMs, such as poor bioavailability and toxic side effects, the thesis provides an in-depth analysis of LAP as an alternative biologics’ delivery vehicle. Utilizing a multidisciplinary research approach, the study reveals the cryo-EM structure of LAP at 2.9 Å resolution, elucidating its multimeric formation and interaction with Hsp60 through electrostatic forces, as supported by computational modeling.</p><p dir="ltr">The functional efficacy of LAP is further established through experiments demonstrating its capability to transport drug analogs across epithelial cell monolayers comparably to established TJMs. Moreover, <i>in vivo</i> studies using a mouse oral gavage model show that LAP significantly enhances the blood levels of peptide drugs without triggering inflammatory responses or harming tight junction architecture. This thesis ultimately positions the LAP-Hsp60 complex as a promising TJM candidate, offering an innovative means for enhancing oral drug delivery and maintaining epithelial barrier integrity.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/24744570 |
| Date | 06 December 2023 |
| Creators | Manalee Samaddar (17562165) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | In Copyright |
| Relation | https://figshare.com/articles/thesis/_b_Structural_and_Functional_Assessment_of_b_b_i_i_b_b_i_Listeria_i_b_b_b_b_Adhesion_Protein_as_a_Tight_Junction_Modulator_Toward_a_Safer_and_More_Effective_Oral_Drug_Delivery_System_b_/24744570 |
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