Regulation of epithelial cell polarity and lung disease
Initial Award Abstract
The lung consists of a branching tree of tubes. The final branches end in tiny air sacs. All of the tubes and air sacs are lined by a single layer of cells, called epithelial cells. This layer of epithelial cells forms the crucial barrier between the outside world (that is the air we breath), and the interior of the organism. All of the exchanges between the outside world and the interior take place across this epithelial layer, so its correct functioning is essential to life. To perform this vital function, each epithelial cell is polarized, that is it has an asymmetric organization. Each cell has a surface that faces the lumen and contacts the air. This surface is called the apical surface. The other surface of the cell is called the basolateral surface and it contacts adjacent cells and the underlying tissues of the organism.
The epithelial cells are directly exposed to the harmful and carcinogenic chemicals in tobacco smoke. Damage to the epithelial cells leads to at least two major types of tobacco-related disease. First, most lung cancers arise from epithelial cells. A hallmark of lung cancer is that the cells lose their polarity. Indeed, the degree of loss of polarity correlates with the severity of the disease. Second, Chronic Obstructive Pulmonary Disease (COPD) involves changes to the architecture of the lung, including epithelial polarity. In the form of COPD known as chronic bronchitis, there is an increased proliferation of glands that are associated with the large airways. These glands produce secretions and mucus, and the production of these substances is increased in chronic bronchitis. These glands are also lined by a single layer of polarized epithelial cells, and so understanding their polarity and proliferation is important to understanding chronic bronchitis.
I will study how epithelial cells become polarized. Cell polarity is controlled in most cell types by a master regulator, a complex of proteins known as Par3, Par6, atypical Protein Kinase C (aPKC) and Cdc42. I will study how this complex regulates polarized of epithelial cells. I will grow epithelial cells in the laboratory, in three-dimensional gels. This system replicates the most important features found in epithelial cells in the lung. My results should provide new insights into the pathogenesis and progression of lung cancer and COPD, and may help in discovering new therapeutics, diagnostics, and prophylaxis. |
|Polarity proteins PAR6/aPKC regulate cell death through GSK-3b in 3D epithelial morphogenesis
|Periodical: Molecular Biology of the Cell
|Authors: Minji K, Anirban D, Mostov K