Development of therapeutic bioconjugates for neuroprotection in ischemic stroke.

Zaghmi, Ahlem (2020). Development of therapeutic bioconjugates for neuroprotection in ischemic stroke. Thèse. Québec, Doctorat en sciences de l'énergie et des matériaux, Université du Québec, Institut national de la recherche scientifique, 327 p.

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Résumé

This thesis is written based on the INRS Guide-2019, article-based version in order to fulfill the last requirement of the PhD program. It consists of an abstract (English and French versions), synopsis (required when a thesis or dissertation is written in English), general introduction, general discussion and conclusion, bibliography, and appendix which will be further discussed in below. Synopsis: Includes the main points discussed in the document and explains the working hypotheses, research objectives, methodology, and results in much more detail than the abstract does. Chapter 1: Consists of a review of literature about the ischemia, glutamate excitotoxicity, and enzymatic glutamate degradation approaches. This chapter concludes with a contextualization. Of note, some sections of this chapter are published as part of a manuscript accepted for publication in Biomaterials (Appendix C). Chapter 2: Presents concepts related to PEGylation, its benefits and its drawbacks. This chapter ends with a research proposal, the main hypothesis, and objectives. The figures used in Chapter 1 and 2 are either from the literature or made by me (with BioRender) in order to provide further explanation. Chapter 3: Published as Zaghmi, A.; Mendez-Villuendas, E.; Greschner, A. A.; Liu, J. Y.; de Haan, H. W.; Gauthier, M. A., Mechanisms of activity loss for a multi-PEGylated protein by experiment and simulation. Mater Today Chem 2019, 12, 121-131. I was responsible for data collection and analysis as well as the manuscript composition and revision. Andrea A Greschner contributed to manuscript edits and assisted with the PEGylation experiments. Jun Yang Liu was a summer student under my supervision who assisted with some measures of the enzyme activities. Eduardo Mendez-Villuendas performed the simulations with the help and supervision of Hendrick W de Haan. Marc A Gauthier was the supervisory author and was involved with concept formation, manuscript composition and revision. This Chapter starts with a brief contextualization and finishes with a preliminary study introducing the following paper. Chapter 4: Accepted as Zaghmi, A.; Dopico-López, A.; Pérez-Mato M.; Iglesias-Rey R.; Hervella P.; Greschner A. A.; Bugallo-Casal A.; Da Silva A.; Gutiérrez-Fernández M.; Castillo J.; Campos Pérez F.; Gauthier, M. A., Sustained blood glutamate scavenging enhances protection in ischemic stroke. Commun Biol 2020. I participated in the design and conception of the study, carried out most experiments (synthesis, characterisation, and purification of the bioconjugates; in vivo experiences including the functional tests). I also wrote and revised the manuscript. Antonio Dopico-López contributed with the production of the ischemic rat model. María Pérez-Mato contributed with the production of the ischemic rat model and commented on the manuscript at all stages. Ramón Iglesias-Rey and Pablo Hervella helped with technical assistance (mainly for MRI). Francisco Campos Pérez participated to the design and conception of the study, results discussion, and commented on the manuscript at all stages. Marc A. Gauthier was the supervisory author and was involved with concept formation and manuscript composition and revision. Chapter 5: General discussion, conclusion and perspectives. Summarizes the main elements of the articles and how they are related. This discussion also presents the contribution of this thesis to the field, as well as the limitations of this work. Both are framed with possible future directions that can be explored. Chapter 6: Appendix. Contains additional information to complement the body of the text and includes elements that are essential to the understanding of the thesis or to support its argumentation. It further presents scientific papers in which I am first author. - Appendix A: Supplementary information of Paper 1. - Appendix B: Supplementary information of Paper 2. - Appendix C: Review paper, accepted as Zaghmi, A.; Drouin-Ouellet J.; Brambilla, D.; and Gauthier, M. A., Treating Brain Diseases using Systemic Parenterally-administered Protein Therapeutics: Dysfunction of the Brain Barriers and Potential Strategies. Biomaterials 2020. - Appendix D: Data in Brief paper, published as Zaghmi, A.; Greschner, A. A.; Mendez Villuendas, E.; Liu, J. Y.; de Haan, H. W.; Gauthier, M. A., Determination of the degree of PEGylation of protein bioconjugates using data from proton nuclear magnetic resonance spectroscopy. Data Brief 2019, 25. - Appendix E: Book Chapter, published as Zaghmi, A.; Greschner, A. A.; Gauthier, M. A., In vivo properties of therapeutic bioconjugates composed of proteins and architecturally/functionally complex polymers. Polymer-Protein Conjugates: From PEGylation and Beyond 2020, 389-406. Chapter 7: Contains the bibliography used in this thesis. It should be noted that the references used for each scientific paper are included in this chapter (except for Appendix D and E).

Type de document:	Thèse Thèse
Directeur de mémoire/thèse:	Gauthier, Marc Andre
Mots-clés libres:	matériaux; biomatériaux;
Centre:	Centre Énergie Matériaux Télécommunications
Date de dépôt:	21 avr. 2021 14:52
Dernière modification:	19 janv. 2022 19:23
URI:	https://espace.inrs.ca/id/eprint/11748

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