Welcome to the Kalinichenko Lab
Overall Research Goals
The Kalinichenko Lab is interested in transcriptional regulation of endothelial cells during lung development and regeneration, with the overall goal to improve health outcomes of newborns and infants facing life-threatening respiratory conditions, such as: Bronchopulmonary Dysplasia (BPD), Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV), Acinar Dysplasia, Congenital Diaphragmatic Hernia (CDH), Neonatal Pulmonary Hypertension, Acute Respiratory Distress Syndrome (ARDS) and others.
Our notable achievements include: the development of nanoparticle delivery systems for gene therapies in pulmonary endothelial cells; discovery of small molecule compounds targeting endothelial transcription factors; development of cell therapy with donor endothelial progenitor cells to improve the neonatal angiogenesis; and the use of pluripotent embryonic stem cells to create bioengineered lungs using animals as “bioreactors”.
Current Research Projects in the Lab
Nanoparticle delivery of proangiogenic genes and small molecule compounds into the lung microvascular endothelial cells to improve neonatal angiogenesis and alveolarization:
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a fatal congenital disorder caused by inactivating mutations in the FOXF1 gene and is characterized by defects in morphogenesis of pulmonary capillaries, positioning of pulmonary veins, and impaired lobular development. Using CRISPR/Cas9 technology, the lab generated several clinically relevant murine models of ACDMPV. Utilizing these ACDMPV models, the lab showed that nanoparticle-mediated delivery of STAT3, a critical downstream target of FOXF1, increases endothelial proliferation and stimulates neonatal pulmonary angiogenesis. Currently, the team is expanding on this idea by testing nanoparticle delivery of various proangiogenic genes and drugs in ACDMPV and other animal models of pulmonary diseases associated with vascular insufficiency.
Employing specialized alveolar endothelial progenitor cells to increase neonatal angiogenesis:
Using single-cell RNA sequencing of human and mouse neonatal lung tissue, the lab identified pulmonary endothelial progenitor cells (EPCs) that are dependent on FOXF1 and c-KIT to maintain cell survival and proliferation during lung development and lung regeneration after neonatal injury. Transplantation of c-KIT+ FOXF1+EPCs into hyperoxia-injured recipient mice resulted in cell engraftment into the alveolar microvasculature, improving lung angiogenesis and protecting newborn mice from alveolar simplification caused by hyperoxic injury. Currently, the lab is actively involved in employing directed differentiation of embryonic stem cells to generate EPCs in vitro, with the long-term goal of developing an effective cell-based therapeutic for patients with ACDMPV and bronchopulmonary dysplasia (BPD).
Generation of ESC/iPSC-derived lung tissue for organ transplantation:
Pediatric and adult patients with incurable lung diseases die before receiving lung transplants due to the scarcity of donor lungs available for transplantation. The lab is tackling this issue by utilizing blastocyst complementation to generate functional lung tissue in vivo using rodent models and interspecies chimeral. The lab found that murine embryonic stem cells are capable of generating entire lungs when injected into blastocysts of Nkx2.1-deficient mice or rats with lung agenesis. The long-term goal is to generate ESC/iPSC-derived lungs and respiratory progenitor cells for cell- and tissue-based therapies in pediatric and adult pulmonary diseases.
News
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Globally Renowned Research Scientist Joins Phoenix Children’s, University of Arizona College of Medicine – Phoenix
“In a move that will greatly advance pediatric research in Arizona and beyond, Phoenix Children’s and the University of Arizona College of Medicine – Phoenix announced the hire of Vladimir Kalinichenko, MD, PhD, as director for the Phoenix Children’s Research Institute …”
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Twice the Impact
“The most important things for me were the communication with the leadership and their buying into the long-term vision to develop pediatric translational science…”
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University of Arizona College of Medicine – Phoenix receives $3 million NIH grant for lung disease in infants
“The University of Arizona College of Medicine – Phoenix announced Feb. 14 it had received a $3 million grant from the National Institutes of Health to develop new treatment methods for lung disease in premature infants.”