Understanding the role of prenatal stress challenge in modulating airway epithelial function and programming asthma manifestation later in life

• Applicant: Dr. Dimitra Zazara
• Subject Area: Clinical Immunology and Allergology ; Pediatric and Adolescent Medicine ; Pneumology, Thoracic Surgery
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504087704

Asthma is one of the most common medical conditions worldwide. Interestingly, mounting evidence places the origin of asthma in fetal life. Several factors such as maternal smoking or increased maternal stress perception during pregnancy have been linked to asthma manifestation later in the life of the offspring. We have previously shown that an impaired fetal lung development and a disrupted airway epithelium account for the increased risk of postnatal asthma in mice upon prenatal stress exposure. However, the exact mechanistic link between prenatal stress and a poorly developing lung remains elusive. We here hypothesize that an untimely fetal exposure to excessive glucocorticoids - triggered by prenatal stress – impairs lung tissue sensitivity to glucocorticoids later during gestation. Thus, lung maturation is delayed at birth, associated with the long-term consequence of an increased asthma susceptibility later in life. To test this hypothesis, we will use transgenic mice allowing a cell- and time-specific conditional knockout of the glucocorticoid receptor in different epithelial compartments of the developing fetal lung. Following prenatal stress challenge and postnatal asthma induction, we aim to mechanistically characterize the effect of prenatal stress on the developing lung epithelium, uncover the critical time period for such challenges and the distinct cellular population that is mainly implicated in this process. This study will provide us with valuable insight into the fetal origin of asthma and allow us to identify early markers and signs pointing to a high risk for postnatal lung dysfunction and disease. An early detection of potential aberrations in lung development, which could lead to postnatal respiratory morbidities such as asthma, would allow the design of prediction, disease prevention and treatment strategies.

• DFG Programme: Research Grants