Neurotrophin receptor ligands LM11A-31, pro-brain-derived neurotrophic factor, GK-2, and GSB-106, and growth factor interleukin-34 modulate select immune functions of microglia
department or school: Science, Irving K. Barber Faculty of (Okanagan)
department or school: Biology, Department of (Okanagan)
data provider: DSpace
degree campus: UBCO
creator: Lindhout, Ivan Andrew
issued: 2024-06-10T20:18:18Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Microglia provide immune defense in the central nervous system (CNS) through functions that include cytokine and cytotoxin secretion and phagocytosis. However, in several CNS disorders such as Alzheimer’s disease, aberrant activation of microglia causes decreased phagocytic activity and increased neurotoxicity due to the release of cytotoxic reactive oxygen (ROS) and nitrogen (RNS) species and pro-inflammatory cytokines. The growth factor interleukin (IL)-34 and neurotrophins (NTs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), as well as the proneurotrophin proBDNF are important for trophic signaling and regulation of survival and apoptosis in neurons. The effects of these compounds are mediated through the IL-34 receptor, colony-stimulating factor-1 receptor, and the NT receptors (NTRs), tropomyosin-receptor kinase (Trk)A, TrkB, and p75NTR. These growth factors and proBDNF also have profound CNS effects by binding to their receptors on other cell types, including microglia. IL-34, BDNF, and NGF have been shown to have therapeutic potential by reducing microglial immune activation. However, the large size of BDNF and NGF prevents them from penetrating the blood-brain barrier easily. Therefore, small molecules were developed to circumvent these issues while retaining the ability to activate NTR signaling pathways, including the TrkA ligand GK-2, TrkB ligand GSB-106, and p75NTR ligand LM11A-31. In my thesis work, I addressed knowledge gaps surrounding the effects of these three ligands as well as proBDNF and IL-34 on microglial neuroinflammatory functions. Chapter three demonstrates that IL-34 increased phagocytic activity of unstimulated and stimulated microglia, decreased ROS release by primed microglia-like cells, reduced monocyte chemoattractant protein (MCP)-1 secretion by stimulated microglia-like cells, and raised RNS production by unstimulated microglia. In chapter four, I show that LM11A-31 and proBDNF decreased the release of ROS by…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/88451
note: NEUROTROPHIN RECEPTOR LIGANDS LM11A-31, PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR, GK-2, AND GSB-106, AND GROWTH FACTOR INTERLEUKIN-34 MODULATE SELECT IMMUNE FUNCTIONS OF MICROGLIA by Ivan Andrew Lindhout B.Sc., The University of the Fraser Valley, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE COLLEGE OF GRADUATE STUDIES (Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) June 2024 © Ivan Andrew Lindhout, 2024 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis/dissertation entitled: NEUROTROPHIN RECEPTOR LIGANDS, LM11A-31, PRO-BRAIN-DERIVED NEUROTROPHIC FACTOR, GK-2, AND GSB-106, AND GROWTH FACTOR INTERLEUKIN-34 MODULATE SELECT IMMUNE FUNCTIONS OF MICROGLIA submitted by Ivan Andrew Lindhout in partial fulfillment of the requirements of the degree of Master of Science. Dr. Andis Klegeris, Department of Biology Supervisor Dr. Julien Gibon, Department of Biology Supervisory Committee Member Dr. Richard Plunkett, Department of Biology Supervisory Committee Member Dr. Conor Pranckevicius, Department of Chemistry University Examiner iii Microglia provide immune defense in the central nervous system (CNS) through functions that include cytokine and cytotoxin secretion and phagocytosis. However, in several CNS disorders such as Alzheimer’s disease, aberrant activation of microglia causes decreased phagocytic activity and increased neurotoxicity due to the release of cytotoxic reactive oxygen (ROS) and nitrogen (RNS) species and pro-inflammatory cytokines. The growth factor interleukin (IL)-34 and neurotrophins (NTs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), as well as the proneurotrophin proBDNF are important for trophic signaling and regulation of survival and apoptosis in neurons. The effects of these compounds are mediated through the IL-34 receptor, colony-stimulating factor-1 receptor, and the NT …
has type: Thesis/Dissertation
date issued: 2024-09
is shown at: 10.14288/1.0443952
language: eng
degree discipline: Biology
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: Klegeris, Andis
type: Text
identifier URI: http://hdl.handle.net/2429/88451