The Role of Protocadherin-1 in Epithelial Plasticity in Asthma.

Elderman, R. (Robin) (2014) The Role of Protocadherin-1 in Epithelial Plasticity in Asthma. thesis, Medicine.

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Abstract

Asthma is a common chronic disease of the airways affecting up to 300 million people world-wide. Asthma is characterized clinically by variable airway obstruction with a reversible component, and airway hyperresponsiveness triggered by smoke, cold air and allergens such as house-dust mite. Asthma patients experience episodes of cough, wheeze and shortness of breath. Furthermore, airflow limitation may result in severe shortness of breath or induce exacerbations. Asthma is a complicated heterogeneous disease, which is caused by a combination of environmental factors like allergens, air pollution, viral infections and smoking, and genetic factors. Previous studies have investigated the heritability of certain pieces of DNA within families with asthma. This way, they have pointed out certain regions with genes that may cause asthma or one of the traits of asthma like bronchial hyperresponsiveness. Subsequently, it has been investigated if there are DNA variations in these genes that are more frequent in asthmatic subjects than in non-asthmatics. This has led to the discovery of a novel gene for bronchial hyperresponsiveness and asthma, named Protocadherin-1. Protocadherin-1 (PCDH1) belongs to the family of adhesion molecules. Because PCDH1 has a relatively weak adhesion function, it is thought that PCDH1 also performs other functions like signaling. In a previous study, it has been described that the protein molecule PCDH1 can have a physical interaction with the signaling molecule SMAD3. SMAD3 is a molecule that transmits signals from membrane-bound transforming growth factor beta (TGF-β) receptors, which are activated by growth factor TGF-β, to the nucleus of the cell. In the nucleus, SMAD3 activates the transcription of several genes. This allows for several processes to take place, such as: (1) repair of epithelium after injury, and (2) the change (transition) of an epithelial cell to a muscle or connective tissue cell (mesenchymal cells) (EMT). Furthermore, it has been shown that SMAD3 may play a role in the differentiation of epithelial cells. By interacting with SMAD3, PCHD1 could affect the restoration of a damaged epithelial layer or the transition of epithelial cells to migrating cells (EMT) and differentiation of epithelial cells. The restoration of a damaged epithelium (wound) consists of several stages. Firstly, the healthy epithelial cells that surround the wound must de-differentiate. Therefore, these cells lose their function as epithelial cells and they obtain a migratory function. This process is similar to EMT. Then, they can begin to move to the location of the wound. Ultimately, these cells must differentiate again to form a functional epithelial cell. PCDH1 could play a role in all these stages of epithelial repair. We start from the assumption that people with asthma that are carrier of base pair changes in the PCDH1 gene have impaired functioning or have reduced expression levels of PCDH1. As a result, processes such as adhesion and differentiation are disrupted, which impair the recovery of the epithelium after injury and the proper differentiation of epithelial cells. This can lead to an epithelial layer that remains in the repair state. This causes the epithelial barrier to become weakened, allowing allergens and other environmental factors to penetrate more easily and thereby causing a chronic reaction, which can eventually lead to bronchial hyperresponsiveness and asthma.

Item Type:	Thesis (Thesis)
Supervisor name:	Koppelman, Prof. G.H. and Kallenberg, Prof. C.G.M.
Supervisor name:	Hackett, Dr. T.L. and University of British Columbia and Centre of Heart Lung Innovation
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:58
Last Modified:	25 Jun 2020 10:58
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1853

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