Chronic Obstructive Pulmonary Disease (COPD) is the 3rd leading cause of death in the US with a large subset of patients exhibiting chronic bronchitis. At this time we have no medications to cure chronic bronchitis (CB). In the U.S., cigarette smoke (CS) is the primary insult, leading to CB; yet, we do not understand how CS alters the epithelium to promote the development of mucus. In our work, we found that chronic CS causes stiffening of the epithelial cell in order to impact on its shape and decrease cell-cell adhesion proteins such as E-cadherin, to prevent the formation of contacts between neighboring cells. In this proposal, we will decipher the effects of altered actin-myosin II contractility. We propose that this increase in cell contractility decreases the polarity of the epithelial cell to promote cell-signaling events, including the activation of the epithelial growth factor receptor (EGFR). EGFR activation, in turn, leads to changes associated with chronic bronchitis, such as the increase in Muc5AC production. We propose to study pharmacologic interventions to alter actin-myosin contractility to study its effects on E-cadherin, cell-cell adhesion, cell polarity with EGFR activation and Muc5AC production.
In Aim 1, we will determine if CS causes myosin II-driven increases in actin-myosin contractility to decrease membrane E-cadherin and disrupting cell-cell adhesion. Specifically, we will dissect the molecular mechanisms by which CS increases actin-myosin contractility, and determine if manipulating this increase will alter E- cadherin levels and cell-cell adhesion.
In Aim 2, we will determine if CS-induced increased actin-myosin II contractility causes the epithelial cell to increase aberrant EGFR activation. Specifically, we will determine if increased contractility alters the polarity of the epithelium to promote EGF receptor-ligand interaction on either the apical or basolateral membrane to increase EGFR activation.
In Aim 3, we will determine if, in a mouse model, decreasing the actin-myosin contractility will reverse EGFR activation and Muc5AC production by the epithelium after chronic CS. We will determine if inhibiting actin-myosin II contractility in vivo prevents or abrogates the CS-induced increase in Muc5AC and mucin production evident in mice after chronic CS exposure. We have found that E-cadherin knockdown promotes EGFR activation in mice. Using our newly established model to knockdown E-cadherin in the mouse lung epithelium, we will assess if actin-myosin contractility is upstream of decreases in E-cadherin to cause EGFR activation and increased Muc5AC. This is a five year grant proposal from an Early Stage Investigator.
Chronic Obstructive Pulmonary Disease (COPD) is the 3rd leading cause of death in the United States results from airway epithelium damage, which is often induced by cigarette smoke. In this proposal, we will decipher mechanisms by which CS alters epithelial integrity by stiffening the epithelial cells to decrease E-cadherin and diminish cell-cell adhesion and contribute to the progression of chronic bronchitis. We will study potential therapeutic strategies to decrease the mucus production in response to chronic cigarette smoke.
| Sidhaye, Venkataramana K; Nishida, Kristine; Martinez, Fernando J (2018) Precision medicine in COPD: where are we and where do we need to go? Eur Respir Rev 27: |
| Miller 3rd, Russell R; Lopansri, Bert K; Burke, John P et al. (2018) Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU. Am J Respir Crit Care Med 198:903-913 |
| Sidhaye, Venkataramana K; Biswal, Shyam (2018) Chronic Obstructive Pulmonary Disease: Abandoning the ""Streetlight Effect"". Am J Respir Crit Care Med 198:697-698 |
| Nishida, Kristine; Brune, Kieran A; Putcha, Nirupama et al. (2017) Cigarette smoke disrupts monolayer integrity by altering epithelial cell-cell adhesion and cortical tension. Am J Physiol Lung Cell Mol Physiol 313:L581-L591 |
| Brune, Kieran; Frank, James; Schwingshackl, Andreas et al. (2015) Pulmonary epithelial barrier function: some new players and mechanisms. Am J Physiol Lung Cell Mol Physiol 308:L731-45 |
