Principal Investigator
Life-saving respiratory support (e.g. mechanical ventilation or oxygen supply) and adverse metabolic influences during a critical window of lung development induce neonatal chronic lung disease (CLD). The molecular, cellular, structural and functional characteristics of neonatal CLD show great similarity to the hallmarks of aging. The purpose of our research is to investigate premature activation of aging-associated processes in the developing and aging lung across ages and generations in order to define novel preventive and therapeutic strategies for neonatal CLD, promoting lung health.
The clinical significance of chronic lung disease (CLD) and the lack of preventive and curative strategies highlight the urgent need to unravel its early molecular origins in order to identify novel therapeutic targets. To this end, our research team investigates converging molecular mechanisms by which mechanical ventilation, oxygen, and obesity disrupt normal lung development, cause lung injury, promote premature cardiopulmonary aging and determine the susceptibility to cardiopulmonary diseases inter- and transgenerationally.
The purpose of our research is to identify converging pathways of perinatal injury and premature cardiopulmonary aging that determine the susceptibility to chronic lung diseases across ages and generations, ultimately enabling us to identify new therapeutic targets for preserving and promoting lung health.
The research team has identified molecular mechanisms that are central in aberrant lung development and early origins of chronic cardiopulmonary disease. Our goal is now to unravel the molecular mechanisms underlying the exposome-lung interplay across ages and generations that drive premature lung aging and determine susceptibility to chronic cardiopulmonary diseases. The Alcázar group has the vision to develop new strategies to promote lung health early in life and to avoid premature lung aging in order to prevent chronic lung disease.
Our research group demonstrated that exposure of the developing lung to prolonged hyperoxia, mechanical ventilation, malnutrition or obesity drives activation of aging processes and causes neonatal chronic lung disease. Inflammatory processes along with dysregulation of transcription factors (e.g. Klf4, FoxO family) are key mechanisms of aberrant lung development and neonatal chronic lung disease. These findings are closely related to hallmarks of aging, including altered nutrient sensing, loss of stemness, DNA damage response (DDR), senescence and matrix remodeling.
Our research team has identified inflammatory processes, dysregulated expression of transcription factors (e.g. Klf4, FoxO1), increased DDR and matrix remodeling along with a loss of stemness as key mechanisms after perinatal injury with inter- and transgenerational impact. These findings are closely related to the hallmarks of aging. Based on these findings, we now pursue three aims: first, we will study animal models of premature lung aging using a cell-specific deletion of the DNA excision repair protein Ercc1. Second, we will decipher signaling hubs of the alveolar regenerative niche on a single cell level in neonatal and adult chronic lung disease as well as in naturally aged lungs, including new multiple-hit models. Finally, we will target specific novel molecules and transcription factors to prevent premature aging and cardiopulmonary diseases. To this end, we employ a variety of techniques, ranging from in vitro and ex vivo murine and human models (e.g., precision cut lung slices) to genetically modified mice and neonatal lung models, along with state-of-the-art approaches in systems biology. Ultimately, our team envisions developing new strategies to promote lung health early in life and preventing cardiopulmonary diseases across ages.
Principal Investigator