*Funded PhD Studentship Opportunity

Investigating targeted delivery of pro-repair factors to the lungs

About the Project

3-year NHLI-funded PhD post-starting Spring 2023

Summary of Research

Applications are invited from candidates with a Masters degree and undergraduate training in a biological science or bioengineering discipline for a PhD to investigate targeted delivery of pro-repair factors to the lungs.

The studentship will be funded for three years with a tax-free bursary of £19,668 per annum plus tuition fees. This studentship is based in the National Heart and Lung Institute at Imperial College London and will be supervised by Dr Charlotte Dean and Dr Matthew Hind.

The lungs are capable of intrinsic repair however, in some people, disruption of these repair processes leads to disease caused either by lack of repair, or an overactive repair response. There are no curative treatments available for many prominent lung diseases including Chronic Obstructive Pulmonary Disease, Adult Respiratory Distress Syndrome and Bronchopulmonary Dysplasia.

Regenerative biology now offers real therapeutic potential to repair or regrow damaged lungs. The aim of the lung development and repair group is to identify and develop regenerative medicine treatments for the lungs that can be used to repair damaged lung tissue and ameliorate diseases.

This PhD project will investigate strategies to target delivery of pro-repair treatments to the lungs. The student will investigate methods to encapsulate pro-repair factors in nanoparticles or hydrogels to extend the efficacy of the pro-repair signals and allow their precise targeting to the lung alveoli. The project will utilise a variety of cutting-edge models, including 3D lung slices to investigate ways to combine potential repair treatments with bioengineering approaches to stimulate optimal lung repair.

The student will be based in the Cardio-Respiratory Section within the National Heart and Lung Institute, which provides an exciting environment, with state of the art facilities and excellent opportunities for PhD student training including research seminars. All students will belong to Imperial’s award-winning Graduate School which provides a comprehensive Professional Skills Programme.

How to Apply

Applicants must hold, or expect to obtain, a first or upper second-class undergraduate degree or UK equivalent, along with a Masters, both in an appropriate subject from a recognised academic institution.

To apply please email the following information to c.dean@imperial.ac.uk with:

  • Curriculum Vitae (max 2 pages)
  • Personal statement (1 page)
  • Name, address, telephone number or email of two referees. At least one of which must be academic.

Applicants unable to attend interview in person will undergo an online interview and be invited for a second face-to-face meeting before confirmation of offer.

Eligibility and funding notes

This studentship is open to home and international students

The successful candidate will receive a bursary of £19,668 per annum plus tuition fees for home students. Successful non-UK students will be offered a bursary with a contribution of £20,000 p.a. towards international tuition fees and will be expected to cover the remaining fees themselves.

Please note that candidates must fulfil College admissions criteria.

Application deadline: 30th November 2022

Funding to investigate the capacity of Wnt5a to repair damaged lungs

The project combines our long-standing interest in determining how Wnt signalling contributes to lung development and repair with bioengineering approaches to target protein delivery to the lungs.

We will determine whether administering Wnt5a (a potential pro-repair protein) to the lungs can strengthen the capacity that the lungs already have to repair themselves. This protein has been shown to stimulate lung stem cells after injury occurs and it is these stem cells that are needed to drive the lung repair process. However we don’t yet understand exactly how the Wnt5a protein carries out this key role and this is what we will determine. We will use time-lapse imaging to video the response of lung cells to Wnt5a treatment and track exactly how this protein stimulates repair. As part of this proposal we will also encase Wnt5a protein in tiny particles of gel and formulate a Wnt5a-gel treatment that can be administered to the lungs to stimulate repair. Encasing Wnt5a in a degradable gel will enable sustained and targeted administration of this treatment.

Dr Sally Kim has been integral to the development of this project which she will co-lead through her role as a researcher co-investigator.

NHLI Research Away Day 2022

NHLI Research Away Day 2022 at the Queen Elizabeth II Conference Centre, London.

After being postponed for 2 years, NHLI Research Away Day was back again!

The Away Day was held on a beautiful day on Friday 17 June 2022 at the Queen Elizabeth II Conference Centre. It was a great opportunity for all staff and students to meet colleagues and to learn the breadth of research across NHLI!

Dr Sek-Shir Cheong gave a talk on ‘Temporal Control of DNA recombination and mRNA delivery in ex vivo Precision-Cut Lung Slices’, describing novel methods that our lab recently established to manipulate genes/targets in adult tissue-based models.

The Frontiers Editor’s Pick with our article is now published as an e-book

The “Editor’s Pick 2021: Highlights in Cell Adhesion and Migration” collection by the Frontiers in Cell and Developmental Biology that includes our article ‘The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling’ is now available as an e-book!

A comprehensive summary of the findings and impacts of our study by the Frontiers editors can be found on Page 7 in the e-book. To read the full article, go to Page 128-146.

MSc project on ‘Investigating lung architecture and development in Down syndrome mouse mutants’

“I was made to feel a part of the team as I attended weekly laboratory meetings with the group, which enabled me to keep up with and gain an understanding of the current research” – Onyinyechi

“As part of my master’s degree in Cardiovascular and Respiratory Healthcare at Imperial College London, I spent four months with the Dean group. Here I undertook a research project that investigated lung development in mouse models of Down syndrome. I was supervised by Charlotte Dean and Sek Shir Cheong who taught me how to analyse sections of lung histology using the software Fiji, as well as how to use a range of scientific databases for genetic analysis.

The research we carried out was important in adding to the small number of studies that had previously investigated lung development in Down syndrome. In our study, we used a range of mouse models which all had three copies of different portions of chromosome 21. This allowed us to narrow down and identify the region of chromosome 21 that was critical in the development of the abnormalities found in the lung histology of these mouse models and the possible candidate genes causing them.

I was made to feel a part of the team as I attended weekly laboratory meetings with the group, which enabled me to keep up with and gain an understanding of the current research taking place at the lab. Additionally, observing presentations, as well as delivering some myself to the group, helped me to develop my presentation skills and allowed me to progress quicker as I received useful and regular feedback. I had a great time working at the lab, especially as I had not done any work like that before.”

– Onyinyechi

MSc project on ‘Investigating lung repair: a live imaging approach’

“My time in the Dean lab allowed me to develop a deeper understanding into how ideas are developed in the lab and how much collaboration is involved in research.” – Lauren

“For my master’s thesis I was lucky enough to undertake a 6-month research project with the dean lab. This experience was incredible, for the first time I was truly integrated into a labs’ research. For my project I was able to work with the on the Acid Injury Repair (AIR) model. This novel model uses hydrochloric acid to mimic lung injury and allows for the study of lung repair and regeneration. Working with Rosin Mongey, who established the AIR Model, I tested ways to image dynamic processes happening in the injured tissue.

Throughout my project I learnt new techniques and concepts. Thanks to the great supervision of Rosin and the FILM department, I became confident with microscopy, an area I knew little about. As microscopy is a central technique in biological research, these newly developed skills will help me in future research.

Alongside my lab work, I was invited to attend weekly lab and section meetings. These meetings helped to highlight the collaborative nature of research. In lab meetings I was kept up to date with the labs work and was able to present and receive feedback on my own, whilst in section meetings, I learnt about the research being performed by other groups.

My time in the Dean lab allowed me to develop a deeper understanding into how ideas are developed in the lab and how much collaboration is involved in research. I hope that the skills I have learnt during this project will help me in a future research career.”

– Lauren

A breath of fresh ‘AIR’ in the study of lung repair and regeneration

A lung slice showing isolated areas of damaged (purple) and undamaged (yellow) tissue

 

Studying the mechanisms of lung repair and regeneration in the human lungs is challenging given their critical role. We have developed a new model, using slices of lung tissue, that can be used to study lung repair and regeneration. The Acid Injury and Repair (AIR) model works by using hydrochloric acid to injure a small part of the tissue slice whilst the surrounding area remains uninjured. This mimics the pattern of injury often observed in lung diseases. The AIR model enables tracking of different cell types, including stem cells as well as providing a platform to test potential new treatments to repair the lungs.

Researchers Sally Kim and Roisin Mongey worked on developing and validating this new tool which was recently published in Biomaterials. You can read about their work on the Imperial Faculty of medicine blog http://wwwf.imperial.ac.uk/blog/imperial-medicine/2021/01/13/a-breath-of-fresh-air-in-the-study-of-lung-repair-and-regeneration/

VANGL2 (Van Gogh-like 2): In Control of Mechanosignalling

Our new research article “The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling” has been published in Frontiers in Cell and Developmental Biology. 

In this study, Dr Sek Shir Cheong discovers how a mutation in the VANGL2 gene (Vangl2Lp), in mutant mice, interferes with normal mechanosignalling and directed cell migration which contribute to abnormal formation of alveoli, the site of gas exchange in the lungs. Mechanosignalling, “mechano-signalling”, simply put, is a signalling process induced by mechanical forces.

By monitoring in real time the movement of alveolar epithelial cells (an important cell type that form alveoli) in slices of lung tissue, we found that cells from the Vangl2Lp/+ mutant mice had slower and more restricted movement compared to cells from normal healthy mice. This resulted in fewer alveoli being formed, which reduces lung function in the mutant mice. To help us understand what causes the abnormal movement in these mutant cells, we isolated epithelial cells from the tracheas and lungs of Vangl2Lp/+ mutant mice, and labelled different components in the cells using antibodies. This process revealed that the Vangl2Lp mutation caused disruption of the actomyosin network (a kind of scaffold present in  cells that is analogous to the musculoskeletal system in the human body), as well as focal adhesions, which function as molecular clutches, enabling cells to attach to their surrounding matrix. In addition we found a reduction in key proteins responsible for mechanosignalling within the lung epithelial cells. All of these abnormalities leads to the the cells being floppy as they are unable to generate force, thereby affecting their ability to move or migrate which is particularly important during the process of lung formation or lung repair after injury. 

Lastly, we tested a drug WNT5A, a molecule that belongs to the same pathway as VANGL2, and showed that it could improve wound healing ability in the mutant cells, suggesting that WNT5A could be a potential target for lung repair. 

This article highlights a previously unknown role of VANGL2 in command and control of mechanosignalling.

Comparison of cellular mechanics in wildtype and Vangl2Lp cells.

 

Dr Bethany Taylor talks about her summer project in the Lung Development and Repair group and her Thorax publication

During my second year of medical school I decided that I wanted to gain some lab experience over Summer, as I realised medical research was an area I’d like to explore further. I was very fortunate to arrange to spend my Summer in the Dean lab and subsequently worked with Charlotte and Matt to design a project that would contribute to the labs work in investigating the mechanisms underlying Congenital Pulmonary Airway Malformation (CPAM). I applied for and gratefully received a Wellcome Student Scholarship to facilitate this, producing a report based on my findings. I found it a fantastic experience working within the research team and gained valuable insight into clinical academia through collaborating with clinicians at the Royal Brompton Hospital.

I have subsequently presented the results of my project at the 2019 Pathology Society Winter meeting held at the Royal Society of Medicine, and this year our article was published in BMJ Thorax. DOI: 10.1136/thoraxjnl-2020-214752.

My experience in the Dean lab has been integral to informing my choice to pursue academic research alongside my clinical work. I have since completed my BSc at Imperial in Cardiovascular Sciences, during which I conducted a lab project at Tokyo Medical and Dental University, and I am currently working as an academic foundation doctor in which I will complete my academic rotation in transplant and regeneration at Addenbrooke’s hospital, Cambridge.

Taylor B et al. Mechanism of lung development in the aetiology of adult congenital pulmonary airway malformations. Thorax 2020

Lung Development Genes and Adult Lung Function

A new study cross-disciplinary study from several groups in NHLI demonstrates the importance of lung development genes in regulating adult lung function. This project used UK Biobank to investigate whether lung development genes influence adult lung function. Future experimental investigation of these developmental pathways could lead to druggable targets to improve lung function.

Am J Respir Crit Care Med. 2020 May 11. doi: 10.1164/rccm.201912-2338OC. Online ahead of print.PMID: 32392078