Darryl Knight


Research Interests

Airway Disease
Lung and airway remodelling
Respiratory diseases

Relevant Degree Programs


Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2019)
Regulation of Basal Cell Plasticity: Implications for Airway Epithelial Remodeling in Asthma (2014)

Asthma is characterized by reversible airflow limitation, airway inflammation and remodeling, which includes increased smooth muscle mass, sub-epithelial fibrosis, goblet cell metaplasia and loss of columnar epithelial cells. Basal cells are progenitor cells of the pseudostratified airway epithelium that undergo distinct phenotypic transitions to maintain epithelial homeostasis following damage. We hypothesized that differentiation of epithelial basal cells is defective in asthma, leading to impaired repair. We used three distinct in vitro models of human airway epithelial basal cell plasticity – epithelial-mesenchymal transition (EMT), repair of mechanical scratch wounds, and differentiation at air-liquid interface – which together provide a complete overview of basal cell function in epithelial repair. In Chapter 3 we assessed the ability of transforming growth factor (TGF)-β₁ to induce molecular reprogramming indicative of EMT and found that basal cells from asthmatic and non-asthmatic patients undergo TGFβ₁-induced EMT. However, an expanded population of basal cells in differentiated epithelial cultures from asthmatic donors led to an increased EMT response. In Chapter 4 we found that inhibition of ΔNp63α impaired restitution of scratch wounds in monolayer culture, due to decreased proliferation. Additionally, ΔNp63α regulated several genes known to be involved in epithelial repair, including β-catenin, epidermal growth factor receptor, and jagged1. In Chapter 5 we found that basal epithelial cells from asthmatic donors with (+) and without (-) exercise-induced bronchoconstriction (EIB) were impaired in the transition to a ciliated but not goblet cell phenotype in an air-liquid interface (ALI) model of mucociliary differentiation. EIB(-) asthmatics also had an expansion of the basal cell population and shorter cilia. In Chapter 6, we used an unbiased RNA sequencing approach to identify aberrant expression of pathways involved in actin cytoskeleton dynamics and cellular metabolism that were distinctly different in EIB(-) and EIB(+) asthma during mucociliary differentiation. We also identified a miRNA-mRNA network that regulates the epithelial transition from proliferation to differentiation. This thesis provides compelling evidence that lineage commitment and molecular reprogramming in basal cells are skewed in asthma to favour epithelial plasticity in response to TGFβ₁, rather than mucociliary differentiation, and that epithelial remodeling is more pronounced in the EIB(-) phenotype of asthma.

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Master's Student Supervision (2010 - 2018)
Inhibition of STAT3 Decreases OSM Induced EDA-FN Expression in Human Lung Fibroblasts (2011)

Fibrosis is excessive deposition of connective tissue components that results in the destruction of normal tissue architecture and compromises organ function. When fibrosis occurs in the major organs such as the lung, for example in idiopathic pulmonary fibrosis (IPF), it inevitably leads to organ failure and premature death of the afflicted individual. The development of fibrosis follows a similar pathway to normal wound healing, although there is chronic progression of the disease without resolution, suggesting the fine control of cellular functions that occur during wound healing is disturbed. Determining where this control is lost is paramount to preventing and treating this condition. Fibroblasts are the main cell type responsible for extracellular matrix (ECM) production. The transcription factor signal-transducer-and-activator-of-transcription-3 (STAT-3) regulates genes involved in cell differentiation and wound healing. It has been shown that fibroblasts isolated from normal and IPF lungs differ in STAT3 dependent interleukin-6 (IL-6)/glycoprotein 130 (gp130) cell signaling and proliferation. Therefore, we aimed to evaluate whether STAT3 inhibition could decrease expression of ECM proteins, including collagen and extra-domain A fibronectin (EDA-FN) in human lung fibroblasts. We also sought to examine the effect of knocking down STAT3 function on fibroblast proliferation. Cells were exposed to Oncostatin-M (OSM) or IL-6, and collagen-1 and EDA-FN protein expression was analyzed by western blotting, while cell proliferation was assessed by bromo-deoxyuridine (BrdU) incorporation. STAT3 function was inhibited in two ways: Firstly, inhibition with a small molecule inhibitor, STA-21, blocks STAT3 dimerization and nuclear translocation and secondly, inhibition of STAT3 gene transcription by short interfering RNA (siRNA). Both methods inhibited OSM induced EDA-FN expression and proliferation in human fetal lung (HFL) fibroblasts. However, STAT3 had negligible effects in adult lung fibroblasts. We attempted to resolve the disparate effects by inhibiting another downstream signaling pathway, the extracellular receptor kinase (ERK)-1/2, which is also activated by gp130. In conclusion, OSM induced EDA-FN expression and cell proliferation in HFL fibroblasts are dependent upon STAT3 activation. In contrast, STAT3 has minimal involvement in adult cells. The mechanisms underlying these disparate effects remain to be elucidated. Interestingly, inhibiting either STAT3 or ERK1/2 inhibited OSM induced proliferation in HFL fibroblasts.

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Prospective Student Info Sessions

Faculty of Medicine Information Session

Date: Tuesday, 08 December 2020
Time: 11:00 to 12:00
UBC’s Faculty of Medicine is a global leader in both the science and the practice of medicine, and is home to more than 1,700 graduate students across over 20 graduate programs. In this session hosted by Dr Michael Hunt, Associate Dean, Graduate and Postdoctoral Education, we’ll provide an overview of the diverse array of graduate programs available, including cutting-edge research experiences in the biosciences, globally recognized population health education, quality health professional training, as well as certificate and online training options. Dr Hunt will also be joined by program advisors from across the faculty to take an inside look at the application process and provide some application tips to help make your application as strong as possible.

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