The aim of this project is to identify vascular progenitor cells and determine the molecular mechanisms that control formation of pulmonary vasculature during embryonic and postnatal lung development. Our ultimate goal is to develop new treatments for patients with congenital and acquired lung vascular disorders. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal congenital disorder of neonates and infants, which is characterized by severe defects in development of pulmonary capillaries, hypoxemia, lung hypoplasia and structural abnormalities of the genitourinary, gastrointestinal and cardiovascular systems. Due to the severity of developmental defects and progressive respiratory insufficiency in ACD/MPV infants, survival after the first month of birth is rare. While genetic factors associated with ACD/MPV are not fully characterized, heterozygous deletions and point mutations in the forkhead box F1 (FOXF1) gene locus account for approximately 40% of ACD/MPV cases.
My laboratory is investigating molecular mechanisms whereby FOXF1 transcription factor promotes the development of pulmonary vasculature. We are also interested in other members of forkhead box (FOX) family, such as FOXM1 and FOXF2, and their role in lung development and stem cell maintenance. We use unique transgenic and knockout mouse models developed in our laboratory, as well as in vitro cultures and lung tissues from patients with pediatric lung vascular disorders to determine signaling mechanisms and transcriptional networks critical for proliferation, differentiation and migration of endothelial cells during pulmonary vascular development.
R01 HL084151 (PI: Kalinichenko, V.)
Foxf1 transcription factor is expressed in pulmonary mesenchyme and endothelial cells. Foxf1 deficiency disrupts formation of the capillary network in mouse embryos.
Lung cancer is the leading cause of death among cancer patients worldwide with a current 5-year survival rate of 8–12%. Existing treatments for lung cancers have not significantly improved patient survival, leading to a critical need for new therapeutic approaches. Lung adenocarcinoma, the most common type of non-small cell lung cancer (NSCLC), exhibits metastases before clinical symptoms become apparent, thus reducing successful treatment options. NSCLCs arise from pulmonary epithelial cells and are often associated with inactivation of tumor suppressor genes and activating mutations in the Kras oncogene.
In our laboratory, we identified the FOXM1 transcription factor as a critical mediator of aberrant Kras/ERK signaling in lung cancer cells in vivo. Genetic deletion of Foxm1 gene from respiratory epithelial cells completely abrogated the initiation of lung tumorigenesis by an activated KrasG12D transgene. We are investigating molecular mechanisms whereby the Kras/ ERK/ FOXM1 signaling pathway induces formation of lung cancer and promotes proliferation of cancer stem cells. We are also developing novel small molecule inhibitors to target FOXM1 in lung cancer. Based on the critical importance of FOXM1 for Kras signaling in mouse lung cancer models, inhibition of FOXM1, either alone or in combination with other anti-cancer drugs, could be beneficial for treatment of human NSCLC lung cancers with activating mutations in the Kras oncogene.
Genetic inactivation of the Foxm1 gene in respiratory epithelial cells of mouse lungs prevents development of lung tumors driven by the oncogenic KrasG12D.
Chronic airway disorders, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and asthma, are associated with persistent pulmonary inflammation and goblet cell metaplasia, contributing to significant morbidity and mortality worldwide. While the molecular pathogenesis of these disorders is actively studied, little is known regarding the transcriptional control of goblet cell differentiation and mucus hyperproduction. We recently showed that pulmonary allergen sensitization induces expression of FOXM1 transcription factor in airway epithelial cells, which in turn stimulates differentiation of airway Clara cells toward a goblet cell fate. Conditional deletion of Foxm1 from Clara cells inhibits goblet cell metaplasia in mouse asthma models. We are investigating molecular mechanisms and transcriptional networks critical for differentiation of goblet cells with the ultimate goal to develop new therapeutic agents capable of inhibiting goblet cell metaplasia and mucus hyperproduction in patients with chronic pulmonary diseases.
R01 HL123490 (PI: Kalinichenko, V.)
Foxm1 transcription factor is expressed in subsets of airway Clara cells and goblet cells of patients with severe asthma as well as lungs of mice with experimental asthma.