000011357 001__ 11357 000011357 005__ 20240523045708.0 000011357 0247_ $$2doi$$a10.6082/uchicago.11357 000011357 041__ $$aen 000011357 245__ $$aEngineering Approaches for the Treatment of Neuroinflammation 000011357 260__ $$bThe University of Chicago 000011357 269__ $$a2024-03 000011357 300__ $$a186 000011357 336__ $$aDissertation 000011357 502__ $$bPh.D. 000011357 520__ $$aThe overall goal of this thesis is to develop engineering approaches for the treatment of multiple sclerosis (MS), an autoimmune disease of the central nervous system. For this purpose, we employ both chemical conjugation and protein engineering strategies to prolong the bioavailability and in vivo half-life of two immunoregulatory molecules. We then evaluate the ability of these engineered molecules to treat experimental autoimmune encephalomyelitis (EAE), a murine model of neuroinflammation, and characterize their respective impact on the immune system. In Chapter 1, we introduce mechanisms of self-tolerance and immunological drivers of autoimmunity, particularly in the context of MS. We then describe the immunopathology MS, and introduce murine models of neuroinflammation that recapitulate several features of MS. Lastly, we discuss the current standards of care and identify areas of unmet need in MS drug development. In Chapter 2, we develop serine butyrate (SerBut), an amino-acid conjugated butyrate prodrug, by esterifying butyrate to serine. First, we characterize the bioactivity and biodistribution of SerBut. We then evaluate the prophylactic efficacy of SerBut in EAE. We subsequently quantify immunological changes induced by SerBut in the CNS draining lymph nodes, spleen, and spinal cord. We also study the impact of SerBut administration on global immune responses to vaccination. In Chapter 3, we develop serum albumin interleukin-33 (SA IL-33), a recombinant fusion protein of the blood protein, serum albumin, and the immunoregulatory cytokine, interleukin-33. First, we characterize SA IL-33 bioactivity, biodistribution, and toxicity. We then evaluate the prophylactic and therapeutic efficacy of SA IL-33 in chronic and relapsing-remitting EAE. We subsequently quantify immunological changes induced by SA IL-33 in the CNS draining lymph nodes, spleen, and spinal cord. In Chapter 4, we summarize the key findings of this thesis and describe opportunities for future investigation in the areas of protein and metabolite engineering for neuroimmunomodulation. 000011357 542__ $$fUniversity of Chicago dissertations are covered by copyright. 000011357 650__ $$aBioengineering 000011357 650__ $$aImmunology 000011357 653__ $$aAutoimmune Diseases 000011357 653__ $$aCytokines 000011357 653__ $$aInflammation 000011357 653__ $$aMetabolites 000011357 653__ $$aMultiple Sclerosis 000011357 653__ $$aProtein Engineering 000011357 690__ $$aPritzker School of Molecular Engineering 000011357 7001_ $$aBudina, Erica$$uUniversity of Chicago 000011357 72012 $$aJeffrey A. Hubbell 000011357 72014 $$aJeffrey A. Hubbell 000011357 72014 $$aAnthony T. Reder 000011357 72014 $$aAaron P. Esser-Kahn 000011357 8564_ $$994a184a2-5fcf-44db-9585-ca7d905906c6$$eEmbargo (2026-03-08)$$s51507180$$uhttps://knowledge.uchicago.edu/record/11357/files/Budina_uchicago_0330D_17324.pdf 000011357 909CO $$ooai:uchicago.tind.io:11357$$pDissertations$$pGLOBAL_SET 000011357 983__ $$aDissertation