Predictive biomarkers of pulmonary exacerbations in cystic fibrosis
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Dong, Kang
issued: 2023-10-31T07:00:00Z
issued: 2022
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Pulmonary exacerbations (PEx) are common in cystic fibrosis (CF) and are significant risk factors for lung disease progression. PEx are often diagnosed when a patient presents to clinic with increased respiratory symptoms and decreased lung function. However, changes can sometimes be subtle or the patient can be a poor perceiver of their symptoms, potentially leading to missed or delayed diagnosis of PEx. Blood-based biomarkers reflective of the host immune response and inflammatory activity have the potential to predict PEx in CF. However, due to the poorly defined pathophysiology of PEx, individual candidate biomarkers are unlikely to capture the full spectrum of immune and inflammatory responses in CF. The central hypothesis of this thesis is that by profiling molecules (protein, transcripts, and modifier genes) in blood with unbiased high-throughput ‘omics’ technologies, we can identify blood-based biomarkers to predict PEx risk and PEx-related treatment outcomes in CF. First, I assessed changes in blood proteins in response to IV antibiotic treatment for PEx. Early changes in IGFR2 were associated with symptom improvement by the end of treatment, suggesting its potential to act as a predictive marker of symptomatic treatment response in CF PEx. I further identified blood biomarker candidates (genes and proteins) from CF individuals with paired stable and PEx samples. Based on these candidates, a 16-gene panel and a 9-protein panel were developed predictive of imminent PEx risk (AUCs of 0.88 and 0.83, respectively). I then evaluated blood proteins to predict azithromycin treatment response in CF individuals. Early changes in serum calprotectin were predictive of PEx risk by day 168, indicating that serum calprotectin represents a promising predictive biomarker to identify individuals who derive benefit from azithromycin treatment. Finally, I investigated genetic modifiers of PEx risk in pre-school children with CF and identified the SLC9A3 variant as significant…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/82821
note: PREDICTIVE BIOMARKERS OF PULMONARY EXACERBATIONS IN CYSTIC FIBROSIS by Kang Dong B.Sc., Shanghai Ocean University, 2014 M.Sc., Temple University, 2016 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2022 © Kang Dong, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Predictive Biomarkers of Pulmonary Exacerbations in Cystic Fibrosis submitted by Kang Dong in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Examining Committee: Dr. Bradley Quon, Associate Professor, Department of Medicine, UBC Supervisor Dr. Scott Tebbutt, Professor, Department of Medicine, UBC Supervisory Committee Member Dr. Sharon Dell, Professor, Department of Pediatrics, UBC University Examiner Dr. Najib Ayas, Associate Professor, Department of Medicine, UBC University Examiner Additional Supervisory Committee Members: Dr. Kelly McNagny, Professor, Department of Medical Genetics, UBC Supervisory Committee Member Dr. Andrew Sandford, Professor, Department of Medicine, UBC Supervisory Committee Member iii Abstract Pulmonary exacerbations (PEx) are common in cystic fibrosis (CF) and are significant risk factors for lung disease progression. PEx are often diagnosed when a patient presents to clinic with increased respiratory symptoms and decreased lung function. However, changes can sometimes be subtle or the patient can be a poor perceiver of their symptoms, potentially leading to missed or delayed diagnosis of PEx. Blood-based biomarkers reflective of the host immune response and inflammatory activity have the potential to predict PEx in CF. However, due to the poorly defined pathophysiology of PEx, individual candidate biomarkers are unlikely…
has type: Thesis/Dissertation
date issued: 2022-11
is shown at: 10.14288/1.0421067
language: eng
degree discipline: Experimental Medicine
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: Quon, Bradley S.
type: Text
identifier URI: http://hdl.handle.net/2429/82821