Current Research Projects
The Role of IKK-beta in Mediating Pulmonary Endothelial Angiogenesis
The transcription factor, nuclear factor kappa- B (NFκB) plays a key role in cell proliferation, survival, and inflammation. NFκB is also a key regulator of angiogenesis in wound healing and cancer. While extensive evidence has implicated activation of NFκB in the pathogenesis of lung disease, until recently, a role for NFκB in lung development had not been previously described. Prior work from the Alvira Lab has shown that NFκB is constitutively active in the early alveolar pulmonary endothelium, and that systemic administration of a pharmacologic inhibitor of the NFκB activating kinases, IKKa and IKKβ, durably disrupts alveolarization and impairs primary pulmonary endothelial cells (PEC) survival, proliferation, and migration.
However, definitive evidence confirming a role for IKKb-mediated NFκB activation in lung angiogenesis and alveolarization has been hindered by the embryonic lethality of mice containing constitutive and conditional deletions of key NFκB family members. Moreover, whether IKKa or IKKβ is the primary activating kinase mediating the pro-angiogenic functions of NFκB remains debated. Therefore, in this application we plan to utilize a novel mouse model, recently created in the Alvira lab, containing an inducible, endothelial cell (EC)-specific deletion of IKKβ to determine if EC-specific deletion of IKKβ impairs pulmonary angiogenesis and alveolarization in vivo, and assess whether these IKKβ-dependent effects are mediated via VEGFR2.
How the Lung Microenvironment Alters the Pulmonary Endothelial Angiogenic Phenotype
In contrast to many other organs which complete their development during early embryonic development, a significant component of lung development occurs postnatally during alveolarization, the final stage of lung development that likely extends through the first decade of life. During alveolarization, the gas exchange surface area of the lung increases 35-fold and the pulmonary capillary network by 20-fold. Growth of the pulmonary vascular network by angiogenesis during early alveolarization is an essential component of this process, and impaired angiogenesis disrupts alveolar development, resulting in large, simplified alveoli and decreased surface area to allow efficient gas exchange.
The molecular mechanisms that allow for rapid pulmonary vascular growth during this discrete window of time are not know. Our prior work has shown that primary endothelial cells derived from the early alveolar lung are much more angiogenic than endothelial cells derived from the adult lung. Interestingly, angiogenic signaling pathways can be induced, and angiogenic function enhanced in adult pulmonary endothelial cells exposed to secreted factors found in the lung microenvironment. Current studies in our laboratory are using proteomic and transcriptomic approaches to identify novel angiogenic factors present in the early alveolar lung microenvironment.
Identifying Novel Targets to Treat Preterm Birth
Premature birth is the primary worldwide cause of morbidity and mortality in newborns and now the top cause of child mortality among those younger than 5 years. Chronic lung disease of infancy (bronchopulmonary dysplasia remains the most common complication of premature birth. Economic consequences of prematurity include lengthy neonatal hospitalizations, costs of special education, maternal health care, and diminished work productivity of adult survivors of prematurity. To date, there are no therapeutic strategies that reliably prevent preterm labor and delivery.
During pregnancy, the uterus must first remain quiescent to allow growth of the developing fetus, and then powerfully contract at birth to deliver the infant. Though myometrial quiescence and activation are central to mammalian life, efforts to prevent premature birth have been confounded by an incomplete understanding of the fundamental biology of myometrial contractility.
We recently identified the transient receptor potential vanilloi-4 (TRPV4) channel as a previously unrecognized modulator of myometrial contractility, and a potential new drug target to address preterm labor. Current studies are underway to better understand how TRPV4 expression and activity are regulated in the pregnant and non-pregnant myometrium, and to develop strategies to specifically target TRPV4 inhibitors to the myometrium as a new therapeutic strategy to treat preterm labor.