Targeting telomere dysfunction-related immune- and organ senescence in pulmonary and cardiovascular disease

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Cardiovascular disease (CVD) and lower respiratory tract disease represent by far, the most common causes of death globally and strongly correlate with age. There is solid epidemiological evidence of a tight relationship between lung and (left) heart disease. For example, acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) are known to increase the risk of myocardial infarction (MI) and heart failure while, conversely, chronic heart failure and MI increase the risk of developing pneumonia or ARDS. Importantly, age is one of the single biggest risk factors for both diseases, while telomere shortening and immunosenescence are amongst the key drivers of aging and age-associated disease. However, surprisingly little is currently known about the mechanistic interrelation of the aged immune system with heart and lung disease or the interaction between both illnesses. Traditionally, they have been investigated and treated as separate diseases. A major aim of this project therefore, is to untangle both mechanisms and interactions of the heart-lung axis in ALI and MI and to study telomere dysfunction-related senescence of the immune system, of heart and lungs. Different mouse models of telomere dysfunction related senescence will be employed, in combination with rejuvenation treatments, involving telomerase gene therapy as a therapeutic approach for organ repair. Specifically, telomerase knock-out mice will be used to separate immune- and organ-senescence by transplantation of bone marrow cells with short telomeres into wild-type mice, and bone marrow cells with normal telomere lengths into telomerase knock-out mice. These chimeric mice will be subjected to ALI and MI to investigate the specific contribution of immune- and organ-senescence to injury responses. In addition, a conditional Shelterin (Trf1) knock-out mouse model will be used to induced senescence specifically in the lungs or the heart. Subsequent injury susceptibility and severity in both organs will be tested. Finally, the impact of a previous ALI or MI on the injury responses in heart and lungs, respectively, will be studied, including as well the therapeutic use of telomerase gene therapy for secondary and tertiary intervention in this scenario. The ultimate goal of these studies will be to improve age-related regeneration and survival in both diseases.In summary, this project aims at providing firm experimental validation for the epidemiological evidence of the connection between lung and heart disease. It will lay a foundation for novel preventive and regenerative therapies.