PKN2's Role in Airway Remodelling Mechanisms in Severe Asthma

Open to UK Applicants only.

Supervisors:

• Dr Katy Roach Kmr11@le.ac.uk
• Professor Dominick Shaw Des21@le.ac.uk
• Professor Peter Bradding

Project: 

Project highlights

1. Conduct a novel investigation into PKN2’s role in airway remodelling and asthma pathology using patient-derived samples
2. Explore the functional impact of PKN2 on fibroblast remodelling through molecular, cellular, and ex vivo approaches.
3. Assess PKN2 expression across diverse lung cell types to uncover its broader role in asthma progression and therapy resistance.

Asthma is the world’s most common chronic lung disease, affecting 1:12 UK adults. Worldwide asthma impacts 269 million people causing 400,000 deaths annually. Most patients respond to inhaled corticosteroids (ICS) and bronchodilators but 10% do not. Injectable antibody therapies (biologics) targeting specific molecules in the airways have transformed the treatment of people with severe asthma, however they do not reverse airway remodelling which contributes to fixed airway narrowing. There is therefore an important unmet clinical need for novel therapies that target these aspects of the disease. 

PKN2 (Protein Kinase N2) is a serine/threonine kinase that plays a critical role in various cellular processes, including cytoskeletal reorganization, cell migration, and proliferation. Studies have linked dysregulated PKN2 expression to the pathophysiology of lung diseases such as asthma and idiopathic pulmonary fibrosis (IPF), highlighting its potential involvement in tissue remodelling and fibrosis.

We hypothesise that PKN2 plays a crucial role in airway remodelling processes and could be validated as a clinical measure of airway remodelling in severe asthma. 

We have 3 primary aims:

Aim 1: Investigate PKN2 Expression in Healthy and Asthmatic Lung Tissue 
Assess PKN2 expression levels in airway tissue from healthy individuals and patients with asthma using quantitative PCR.  Determine cellular localization of PKN2 in airway tissue samples and examine changes in PKN2 expression in response to known remodelling mediators in primary human airway fibroblasts. Analyse correlations between PKN2 levels and clinical parameters of airway remodelling (e.g., lung function tests, ECM deposition markers)

Aim 2: Elucidate the Functional Role of PKN2 in Airway Fibroblast Remodelling 
Characterize the impact of PKN2 overexpression on airway fibroblast remodelling properties, including proliferation, differentiation, and ECM deposition. Perform RNA sequencing and proteomic analyses to identify pathways and targets affected by PKN2 activity. 

Aim 3: Validate Clinical Relevance of PKN2 in Airway Remodelling
Quantify PKN2 levels in blood and bronchial wash from severe asthma patients with fixed airflow obstruction and healthy controls. Compare PKN2 expression in matched patient samples to assess consistency and reliability as a measure of remodelling. 

Outcome and Impact: Successful completion of these aims will provide compelling evidence for the role of PKN2 in airway remodelling and its potential correlation with remodelling in severe asthma. This work could guide future diagnostic and therapeutic strategies aimed at mitigating airway remodelling and improving patient outcomes.

Skills and Techniques
The PhD student will gain hands-on experience with a variety of advanced techniques, including tissue culture, quantitative PCR, immunohistochemistry, RNA sequencing, proteomic analysis and ex vivo lung tissue culture. The student will also develop skills in data analysis, statistics and interpretation.

Travel and Conference Opportunities
There is a travel budget available for attending international conferences, providing the student with opportunities to present research findings, gain exposure to cutting-edge science, and engage with the global scientific community.