Dual Impacts of Newly Engineered COX-PGIS Hybrid Enzyme on Cardiovascular and Neuronal Protection

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dc.contributor.advisorRuan, Ke-He
dc.contributor.committeeMemberAronowski, Jaroslaw A.
dc.contributor.committeeMemberDas, Joydip
dc.contributor.committeeMemberEikenburg, Douglas C.
dc.contributor.committeeMemberGao, Xiaolian
dc.creatorLing, Qinglan
dc.date.accessioned2018-11-30T16:41:56Z
dc.date.available2018-11-30T16:41:56Z
dc.date.createdMay 2018
dc.date.issued2018-05
dc.date.submittedMay 2018
dc.date.updated2018-11-30T16:41:56Z
dc.description.abstractStatement of the problem: Non-steroidal anti-inflammation drugs (NSAIDs) are widely used for varieties of inflammatory conditions by inhibiting COX pathway and decreasing the production of downstream prostaglandins, such as PGE2 and PGI2. As neuroinflammation may lead to Alzheimer’s disease (AD), NSAIDs have also been suggested as a prevention or treatment for AD. However, clinical studies did not show effectiveness. To further understand the mechanisms and eventually achieve the goal, it is important to understand the crosstalk of prostanoids in the hippocampus, a major brain area impacted in AD. So far, a major obstacle in that was to mimic the biosynthesis of each prostanoid. Thus, this study intended to accomplish three aims. Specific aim 1: To study the crosstalk of prostanoids in a neuronal cell line by using hybrid enzymes to redirect the synthesis of prostanoids to PGE2 and PGI2, respectively. Specific aim 2: To investigate the crosstalk of prostanoids in primary hippocampal neurons. Specific aim 3: To examine the dual impacts of newly engineered COX-PGIS hybrid enzyme on cardiovascular and neuronal protection in vivo. Procedure or methods: Here, we created Single-Chain Hybrid Enzyme Complexes (SCHECs), COX-2-10aa-mPGES-1 and COX-1-10aa-PGIS, which could control cellular AA metabolites to the desired PGE2 or PGI2, respectively. By using the two hybrid enzymes, as well as synthetic PGE2 and PGI2 analogues, we investigated the crosstalk of PGE2 and PGI2 in hippocampal neuronal cell line, primary hippocampal neurons, and in vivo Alzheimer’s disease model. Results: The hippocampal neurons expressing SCHECs redirected AA metabolism to a PGI2, or PGE2. Overproduced PGI2 exerted survival protection and resistance to Aβ-induced neurotoxicity. The protection mediated by PGI2 might be through IP receptor. Our PGI2-producing transgenic mice exhibited resistance to AA-induced thrombotic stroke and angiotensin-II-induced vascular constriction. The hybrid of PGI2-producing transgenic mice and AD mice showed restored long-term memory in two behavioral tasks. Conclusions: These findings suggested that the vascular mediators, PGI2 and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus, and raised a concern that the widely uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection.
dc.description.departmentPharmacological and Pharmaceutical Sciences, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10657/3469
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectHybrid enzyme
dc.subjectProstacyclin
dc.titleDual Impacts of Newly Engineered COX-PGIS Hybrid Enzyme on Cardiovascular and Neuronal Protection
dc.type.dcmiText
dc.type.genreThesis
local.embargo.lift2020-05-01
local.embargo.terms2020-05-01
thesis.degree.collegeCollege of Pharmacy
thesis.degree.departmentPharmacological and Pharmaceutical Sciences, Department of
thesis.degree.disciplinePharmacology
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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