In patients with asthma mucous cells appear in airways that are normally devoid of these cells. This phenotype is called mucous cell metaplasia (MCM). MCM poses a serious risk because acutely secreted mucus can reduce airflow or can sometimes completely obstruct the airways and lead to death of asthmatics. In addition, epidemiological studies suggest that patients with chronic MCM are at a higher risk of developing lung cancer. During the previous funding period, we discovered that that for the resolution of allergen-induced MCM during prolonged exposure to an allergen, IFN? through STAT1 activation requires Bik, a protein that is anchored in the endoplasmic reticulum (ER). Bak is so crucial for IFN?- or Bik-induced cell death that airway epithelial cells from bak-/- or even bak+/- primary cells are resistant. We found that Bik interacts with the 160 kDa death-associated protein kinase 1 (DAPk), to tether ER and mitochondria, orchestrate the assembly of ERK1/2 and Bak to activate Bak, and facilitate the release of ER calcium. We generated a Bik-derived peptide that similar to IFN? and Bik activates Bak. We also identified a single nucleotide polymorphism (A G) in the intronic region of the BIK gene that reduces Bik expression levels in differentiated normal human bronchial epithelial cells (NHBEs) and is associated with a significant decline in lung function in two cohort studies. Therefore, this renewal application is focused on delineating the molecular interaction of Bik and DAPk to help optimize the generation of improved Bik-derived peptides that restore Bik function in individuals with the BIK variant that causes reduced Bik levels and resolve MCM. We propose the following hypotheses: IFN?- induced cell death is mediated by Bik binding to DAPk to facilitate the activation of Bak, release ER Ca2+ to mitochondria, and initiation of apoptosis. Furthermore, restoring Bik levels in subjects with a BIK gene variant that causes reduced Bik levels can be an effective way to reduce MCM. We will test these hypotheses by: (1) Elucidating the molecular interaction of Bik and DAPk that facilitates assembly of ERK1/2 and Bak to cause activation of Bak, and by testing whether DAPk tethers ER and mitochondria to coordinate the transfer of ER calcium to mitochondria and disrupt the integrity of the mitochondrial outer membrane. (2) Determining whether a peptide derived from Bik restores resolution of MCM in NHBEs with GG and AG compared to AA genotype and whether a Bik-derived peptide reduces MCM and reverses decline in lung function in bik+/+, bik+/-, and bik-/- mice exposed to allergen. Understanding the molecular mechanisms of the resolution process of MCM will allow us to develop more effective peptides for patients with bronchitic asthma and the BIKGG genotype. This strategy may help maximize the effect of reducing excessive mucus in susceptible individuals and help target pre-neoplastic cells that may survive among hyperplastic cells to prevent the development of lung cancer in high-risk individuals.

Public Health Relevance

Patients with bronchitic asthma can have obstructed airways due to acutely secreted mucus and this obstruction can be life-threatening. The proposed studies elucidate cell death processes that reduce mucus- producing cells and will allow us to develop effective treatments by mimicking the normal resolution process of hyperplastic mucous cells. Further, functional studies have helped us to identify a genetic variant that identifies people at risk of decline in lung function and who may benefit from this treatment that facilitates the resolution of mucous cells. This approach could also be useful to eliminate pre-neoplastic cells in patients with increased risk of developing lung cancer.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Noel, Patricia
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Lovelace Biomedical & Environmental Research
United States
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Vazquez Guillamet, Rodrigo; Petersen, Hans; Meek, Paula et al. (2018) Grading Severity of Productive Cough Based on Symptoms and Airflow Obstruction. COPD 15:206-213
Chand, Hitendra S; Harris, Jennifer F; Tesfaigzi, Yohannes (2018) IL-13 in LPS-Induced Inflammation Causes Bcl-2 Expression to Sustain Hyperplastic Mucous cells. Sci Rep 8:436
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