Development of an affinity-guided probe with turn-on fluorescence to selectively label kainate receptors
department or school: Science, Irving K. Barber Faculty of (Okanagan)
department or school: Chemistry, Department of (Okanagan)
data provider: DSpace
degree campus: UBCO
creator: Tardif, Anthony
issued: 2024-03-07T20:29:09Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Kainate receptors (KARs) are classified as one of three main subfamilies of ionotropic glutamate receptors (iGluRs) located in the brain. They have been shown to participate in neurological homeostasis and normal brain development processes such as synapse elimination; however, excessive synapse elimination is a hallmark of neurodegenerative diseases. Despite a strong association between KARs and neurodegeneration, our understanding of the underlying mechanisms that contribute to excessive synapse elimination is hindered by the lack of chemical tools required to study them. The development of new chemical tools to study KARs will provide a better understanding of their role in neurodegenerative processes and help identify therapeutics to treat related symptoms and diseases. This thesis details the synthesis of a fluorescent kainate probe that selectively labels KARs to address this knowledge gap. The kainate probe consists of three smaller molecules; a kainoid ligand, a linker, and a squaraine fluorophore which were all individually synthesized and then coupled to assemble the probe. Chapter 1 provides a brief introduction to kainate receptors and their role in the brain, as well as an overview of fluorescent protein imaging methods and the concept of turn-on fluorescence. Chapter 2 reviews the structural features that are essential to designing kainoid ligands, precedents in the kainoid syntheses, and the synthesis of a novel kainoid analog, (4R)-4-azidokainic acid, to enable late-stage derivatization at the C4 position of kainic acid. Chapter 3 contextualizes the biological applications of squaraine dyes and how they can be utilized to achieve turn-on fluorescence with improved contrast during fluorescent imaging. Next, it describes the syntheses of squaraine and aminosquaraine intermediates, along with an alkyne linker. Chapter 3 concludes with a detailed account of the synthetic steps performed and the challenges faced towards assembling the kainate probe. Overa…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/87546
note: DEVELOPMENT OF AN AFFINITY-GUIDED PROBE WITH TURN-ON FLUORESCENCE TO SELECTIVELY LABEL KAINATE RECEPTORS by Anthony Tardif B.Sc., University of British Columbia (Okanagan), 2019 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE COLLEGE OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) February 2024 © Anthony Tardif, 2024 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis entitled: DEVELOPMENT OF AN AFFINITY-GUIDED PROBE WITH TURN-ON FLUORESCENCE TO SELECTIVELY LABEL KAINATE RECEPTORS submitted by Anthony Tardif in partial fulfillment of the requirements of the degree of Master of Science. Dr. Frederic Menard, Associate Professor, Department of Chemistry, UBC Supervisor Dr. Stephen McNeil, Associate Professor, Department of Chemistry, UBC Supervisory Committee Member Dr. Kevin Smith, Professor, Department of Chemistry, UBC Supervisory Committee Member Dr. Adam Ford, Associate Professor, Department of Biology, UBC University Examiner Dr. John-Tyler Binfet, Associate Professor, Okanagan School of Education, UBC Neutral Chair iii Abstract Kainate receptors (KARs) are classified as one of three main subfamilies of ionotropic glutamate receptors (iGluRs) located in the brain. They have been shown to participate in neurological homeostasis and normal brain development processes such as synapse elimination; however, excessive synapse elimination is a hallmark of neurodegenerative diseases. Despite a strong association between KARs and neurodegeneration, our understanding of the underlying mechanisms that contribute to excessive synapse elimination is hindered by the lack of chemical tools required to study them. The development of new chemical tools to study KARs will provide a better understanding of their role in neurodegenerative processes and help identify therapeutics to treat related symptoms and diseases. …
has type: Thesis/Dissertation
date issued: 2024-05
is shown at: 10.14288/1.0440639
language: eng
degree discipline: Chemistry
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Menard, Frederic
type: Text
identifier URI: http://hdl.handle.net/2429/87546