Unraveling the Signaling Pathways of the Cd200 Activation Receptor Family and Their Implications in Regulating Antitumor Response in Glioblastoma
2020-05
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Unraveling the Signaling Pathways of the Cd200 Activation Receptor Family and Their Implications in Regulating Antitumor Response in Glioblastoma
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2020-05
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Glioblastoma multiforme (GBM) is the most aggressive and incurable primary brain tumor with a current median overall survival of approximately 14 months. Immune checkpoint-based therapy has demonstrated successes in solid tumors including melanoma and lung cancer increasing overall survival, however, it has not been successful in combating Central Nervous System (CNS) tumors. Our studies seek to establish a successful checkpoint inhibitor-based immunotherapy model for treating GBM, and our central hypothesis is, synthetic ligands modulate CD200 activation receptors (CD200ARs) overriding the inhibitory effect mediated by CD200 binding to CD200IR. The CRISPR/Cas9 system was used to generate different murine raw264.7 macrophages (MØs) cell lines expressing different combinations or a single CD200 receptor. The resultant cell lines were stimulated with the synthetic ligand, and the effects of this binding were studied. The main achievements of this research were to demonstrate that CD200ARs stimulated by synthetic peptide-binding couples with DAP10, and stimulates downstream activation of phosphatidylinositol 3-kinase, Vav1, cJUN, and ERK1/2. Second, CD200ARs form complexes (CD200ARs 2&3) to interact with the peptide ligands to optimize the biological function of macrophages. Third, the signals initiated by CD200ARs/DAP10 induce cytokine secretion and immune activation that results in tumor control. Our research reveals the signaling pathway of the CD200 immune checkpoint that leads to activation rather than suppression of immune cells and improves the response of GBM to vaccine-based immunotherapy.
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University of Minnesota Ph.D. dissertation. May 2020. Major: Comparative and Molecular Biosciences. Advisors: Dr. Michael Olin, Dr. G. Elizabeth Pluhar. 1 computer file (PDF); viii, 144 pages + 2 supplementary files.
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Ampudia Mesias, Elisabet. (2020). Unraveling the Signaling Pathways of the Cd200 Activation Receptor Family and Their Implications in Regulating Antitumor Response in Glioblastoma. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/220128.
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