Defining the functional roles of MUC5AC and MUC5B in mucus in respiratory airways
Lead Research Organisation:
University of Manchester
Department Name: Life Sciences
Abstract
Mucus is the jelly-like substance produced by the lungs to defend the body against pollution, bacteria, viruses and other environmental agents. Mucus acts to trap environmental agents and their removal from the lung is made possible by what is known as the ?mucociliary escalator?: Cells lining the surface of the large airways have tiny hairs called cilia which interact with mucus to trap and remove debris from the lungs. The beating action of the cilia moves the mucus up to the throat, where it is swallowed.
Individuals suffering from airway diseases such as asthma, cystic fibrosis and chronic bronchitis face the constant struggle of not only making too much mucus, but that the mucus produced is stickier than normal. Such sticky mucus cannot be moved by the cilia, resulting in the airways becoming blocked.
Mucus is a complex viscous mixture made up of electrolytes, water and extremely large, rope-like molecules called mucins. There are two types of mucins in the mucus of the large airways, MUC5AC and MUC5B. In disease we know that there is a much larger amount of both mucins produced, which contributes to blocking the airways. In addition, recent research suggests that the ratio of MUC5AC and MUC5B in the mucus gel can alter how the mucus is moved by cilia, but exactly how this happens is not currently understood.
In light of this, our principal research question is: Do the two mucins, MUC5AC and MUC5B, make mucus gels which can be moved by cilia with equal efficiency, and do other components of the mucus gel interact with the mucins to alter how mucus is moved?
To answer this question, we are bringing together research teams in Biology and Physics in order to understand the distinct contributions of MUC5AC and MUC5B to the stickiness of the mucus gel. We will also find out what other molecules are critical for creating a moveable mucus gel which can be cleared from the airways. Understanding the organisation of mucus gels in health and disease will enable the design of new treatments for people suffering with airway obstruction.
Individuals suffering from airway diseases such as asthma, cystic fibrosis and chronic bronchitis face the constant struggle of not only making too much mucus, but that the mucus produced is stickier than normal. Such sticky mucus cannot be moved by the cilia, resulting in the airways becoming blocked.
Mucus is a complex viscous mixture made up of electrolytes, water and extremely large, rope-like molecules called mucins. There are two types of mucins in the mucus of the large airways, MUC5AC and MUC5B. In disease we know that there is a much larger amount of both mucins produced, which contributes to blocking the airways. In addition, recent research suggests that the ratio of MUC5AC and MUC5B in the mucus gel can alter how the mucus is moved by cilia, but exactly how this happens is not currently understood.
In light of this, our principal research question is: Do the two mucins, MUC5AC and MUC5B, make mucus gels which can be moved by cilia with equal efficiency, and do other components of the mucus gel interact with the mucins to alter how mucus is moved?
To answer this question, we are bringing together research teams in Biology and Physics in order to understand the distinct contributions of MUC5AC and MUC5B to the stickiness of the mucus gel. We will also find out what other molecules are critical for creating a moveable mucus gel which can be cleared from the airways. Understanding the organisation of mucus gels in health and disease will enable the design of new treatments for people suffering with airway obstruction.
Technical Summary
Mucus accumulation in the airways is a common pathological feature of hypersecretory disease. The physical properties of the airway mucus gel are predominantly determined by two mucins, MUC5AC and MUC5B. Analysis of mucus obstructing the airways in both asthma and chronic obstructive pulmonary disease (COPD) has shown MUC5B to be the predominant mucin. However, the contribution of either mucin species to the properties of the mucus gel in not understood. In this proposal, we will investigate the hypothesis that the specific mucins MUC5AC and MUC5B and their interacting components form mucus gels with different physical properties which affects mucus transport, and hence airway clearance, by cilia action.
To address this important question, we will employ primary airway cells in culture to produce mucus gels with different proportions of MUC5AC and MUC5B. Using a unique combination of biochemical and state of the art biophysical approaches, we will investigate three interlinked questions that are crucial to understanding the role of MUC5AC and MUC5B in this process: (1) Is it the total concentration of mucin, or the proportion of MUC5AC and MUC5B, that is of most importance in determining the physical and hence transport properties of mucus? (2) How do components that interact with mucins affect MUC5AC and/or MUC5B gel properties? (3) Does incomplete mucin maturation contribute to abnormal mucus properties?
This study will thus establish the molecular basis of the structure and organisation of respiratory mucus gels and will help identify changes in mucus gels that contribute to hypersecretory respiratory diseases. The results will provide a basis for identifying the key components that determine the physical properties and stability of mucus gels and identify the molecular mechanisms responsible for the pathological changes in mucus that accompany chronic lung diseases. The new insight from these studies will reveal novel strategies for combating the complications caused by the production of mucus gels incapable of transport and clearance.
To address this important question, we will employ primary airway cells in culture to produce mucus gels with different proportions of MUC5AC and MUC5B. Using a unique combination of biochemical and state of the art biophysical approaches, we will investigate three interlinked questions that are crucial to understanding the role of MUC5AC and MUC5B in this process: (1) Is it the total concentration of mucin, or the proportion of MUC5AC and MUC5B, that is of most importance in determining the physical and hence transport properties of mucus? (2) How do components that interact with mucins affect MUC5AC and/or MUC5B gel properties? (3) Does incomplete mucin maturation contribute to abnormal mucus properties?
This study will thus establish the molecular basis of the structure and organisation of respiratory mucus gels and will help identify changes in mucus gels that contribute to hypersecretory respiratory diseases. The results will provide a basis for identifying the key components that determine the physical properties and stability of mucus gels and identify the molecular mechanisms responsible for the pathological changes in mucus that accompany chronic lung diseases. The new insight from these studies will reveal novel strategies for combating the complications caused by the production of mucus gels incapable of transport and clearance.