Molecular mechanisms regulating lung vasculature in development and disease
Lead Research Organisation:
University College London
Department Name: Institute of Ophthalmology
Abstract
Background:
Lung vasculature develops in a complex network alongside the airways during embryogenesis to facilitate gas exchange after birth. Although the pulmonary and circulatory systems are tightly associated in the lungs, some areas remain avascular to ensure integrity of tissues e.g. the airway smooth muscle coat of the bronchi. Blood vessel patterning is disrupted in asthma, but little is currently known about the molecular mechanisms underlying these changes. Using the embryonic mouse lung as a model, our unpublished data show that class 3 semaphorins (SEMA3E/3C) and their plexin receptor (PLXND1) act to prevent blood vessel sprouting into avascular lung areas. Moreover, a prior study suggested that human asthmatic patients exhibit decreased levels of SEMA3E and PLXND1 in their bronchi compared to control lungs from non-asthmatic patients, but how this observation relates to the aetiology of the disease is unclear (Movassagh et al, 2014). As asthma is characterised by neovascularisation and airway remodelling, I hypothesise that PLXND1 signalling maintains normal lung structure, but that this response is impaired in asthma.
Aims and objectives:
This PhD project will investigate how PLXND1 signalling regulates blood vessel patterning in the developing lung and whether defects in this pathway also contribute to lung diseases with abnormal blood vessel growth and remodelling, for example asthma and pulmonary hypotension. We will use the mouse as a model to compare the expression pattern of class 3 semaphorins and their receptors in embryonic to perinatal and adult lung with immunofluorescence, in situ hybridisation and quantitative RT-PCR. Analysis of full and tissue-specific knockout mice will provide more evidence of individual SEMA3s and PLXND1 contribution to lung vasculature in development and adult homeostasis. Finally, we will collaborate with UCL Respiratory to investigate their expression pattern and levels in patients with lung diseases.
Overall, this project will shed more light on a molecular mechanism important for lung vascularisation, with the ultimate aim to provide novel therapeutic targets for the treatment of lung diseases with dysregulated blood vessel growth.
Lung vasculature develops in a complex network alongside the airways during embryogenesis to facilitate gas exchange after birth. Although the pulmonary and circulatory systems are tightly associated in the lungs, some areas remain avascular to ensure integrity of tissues e.g. the airway smooth muscle coat of the bronchi. Blood vessel patterning is disrupted in asthma, but little is currently known about the molecular mechanisms underlying these changes. Using the embryonic mouse lung as a model, our unpublished data show that class 3 semaphorins (SEMA3E/3C) and their plexin receptor (PLXND1) act to prevent blood vessel sprouting into avascular lung areas. Moreover, a prior study suggested that human asthmatic patients exhibit decreased levels of SEMA3E and PLXND1 in their bronchi compared to control lungs from non-asthmatic patients, but how this observation relates to the aetiology of the disease is unclear (Movassagh et al, 2014). As asthma is characterised by neovascularisation and airway remodelling, I hypothesise that PLXND1 signalling maintains normal lung structure, but that this response is impaired in asthma.
Aims and objectives:
This PhD project will investigate how PLXND1 signalling regulates blood vessel patterning in the developing lung and whether defects in this pathway also contribute to lung diseases with abnormal blood vessel growth and remodelling, for example asthma and pulmonary hypotension. We will use the mouse as a model to compare the expression pattern of class 3 semaphorins and their receptors in embryonic to perinatal and adult lung with immunofluorescence, in situ hybridisation and quantitative RT-PCR. Analysis of full and tissue-specific knockout mice will provide more evidence of individual SEMA3s and PLXND1 contribution to lung vasculature in development and adult homeostasis. Finally, we will collaborate with UCL Respiratory to investigate their expression pattern and levels in patients with lung diseases.
Overall, this project will shed more light on a molecular mechanism important for lung vascularisation, with the ultimate aim to provide novel therapeutic targets for the treatment of lung diseases with dysregulated blood vessel growth.
