Role of oxidative stress in regulating cell death of lung cells and pulmonary disease in A-T

• Applicants: Professor Dr. Ralf Schubert; Privatdozent Dr. Sjoerd van Wijk, since 10/2020
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426710225

Respiratory disease causes significant morbidity in patients with Ataxia telangiectasia (A-T). Oxidative stress and ongoing low-grade inflammation are considered as key factors contributing to the pathogenesis of pulmonary dysfunction in A-T. The serine/threonine kinase ATM functions as a critical regulator of the cell's response to several forms of cellular stress including oxidative stress or DNA damage. As ATM is crucial for mounting an anti-oxidative response, ATM deficiency leads to increased oxidative stress. Cell death pathways are tightly regulated by the cellular redox state, and increased oxidative stress can lead to cell death. Several forms of programmed cell death with distinct signal transduction pathways are currently known, including apoptosis, necroptosis and ferroptosis. However, the question as to how these forms of programmed cell death contribute to the pathogenesis or progression of lung disease in A-T patients has not yet been explored. In project-specific preliminary work, the group of Ralf Schubert demonstrated that Atm-deficient mice exhibit increased oxidative damage in lung parenchyma, a reduced antioxidant capacity and restricted lung function, which were all rescued by administration of the antioxidant Tempol. The group of Simone Fulda recently discovered that ROS are critical regulators of necroptosis and that lung fibroblasts are particularly susceptible to undergo necroptosis in a ROS-dependent manner. Against this background, the complementary expertise of the two principal investigators (Fulda: redox regulation of cell death signaling pathways, Schubert: Atm-deficient in vitro and in vivo models) will be bundled to test the hypothesis that increased oxidative stress upon ATM deficiency induces programmed cell death of lung cells, contributing to tissue injury and lung disease in A-T. Key objectives of the project are (i) to analyze constitutive and ROS-induced oxidative stress, mitochondrial perturbations and cell death in Atm-deficient and wildtype (WT) lung cells, (ii) to investigate distinct programmed cell death pathways (apoptosis, necroptosis, ferroptosis) and inflammation in Atm-deficient and WT lung cells after induction of oxidative stress and (iii) to determine the effects of ROS on lung cell death and pulmonary disease in an Atm-deficient mouse model in vivo. The project is expected to provide novel insights into the molecular mechanisms of oxidative stress-induced programmed cell death and lung tissue injury in A-T. Since regulated forms of cell death can be modulated pharmacologically, the elucidation of redox regulation of these cell death signaling pathways in the pathogenesis of lung injury in A-T is expected to open new perspectives for the development of innovative therapeutic strategies.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Professorin Dr. Simone Fulda, until 9/2020