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

针对肺部和心血管疾病中与端粒功能障碍相关的免疫和器官衰老

• 批准号: 506207541
• 负责人: Professorin Dr. Christina Brandenberger, Ph.D.
• 金额: --
• 依托单位: Institut für Molekulare und Translationale Therapiestrategien
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/506207541?language=en
• 关键词: Targeting; telomere; dysfunction; related; immune

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.

心血管疾病（CVD）和下呼吸道疾病是迄今为止全球最常见的死亡原因，与年龄密切相关。有确凿的流行病学证据表明，肺和（左）心脏疾病之间存在密切关系。例如，已知急性呼吸窘迫综合征（ARDS）或急性肺损伤（ALI）会增加心肌梗死（MI）和心力衰竭的风险，而相反，慢性心力衰竭和MI会增加发生肺炎或ARDS的风险。重要的是，年龄是这两种疾病的单一最大风险因素之一，而端粒缩短和免疫衰老是衰老和年龄相关疾病的关键驱动因素之一。然而，令人惊讶的是，目前对老年免疫系统与心脏和肺部疾病的相互关系或两种疾病之间的相互作用知之甚少。传统上，它们被作为单独的疾病进行研究和治疗。因此，该项目的主要目的是解开ALI和MI中心肺轴的机制和相互作用，并研究端粒功能障碍相关的免疫系统衰老，心脏和肺。将采用端粒功能障碍相关衰老的不同小鼠模型，与年轻化治疗组合，涉及端粒酶基因治疗作为器官修复的治疗方法。具体而言，通过将具有短端粒的骨髓细胞移植到野生型小鼠中，并将具有正常端粒长度的骨髓细胞移植到端粒酶敲除小鼠中，端粒酶敲除小鼠将用于分离免疫衰老和器官衰老。这些嵌合小鼠将经受ALI和MI以研究免疫和器官衰老对损伤应答的具体贡献。此外，将使用条件性Shelterin（Trf 1）敲除小鼠模型来诱导肺或心脏的衰老。随后将测试两个器官的损伤敏感性和严重程度。最后，将分别研究先前的ALI或MI对心脏和肺中的损伤反应的影响，包括在这种情况下端粒酶基因疗法用于二级和三级干预的治疗用途。这些研究的最终目标是改善这两种疾病中与年龄相关的再生和存活率。总之，本项目旨在为肺和心脏病之间联系的流行病学证据提供可靠的实验验证。它将为新的预防和再生疗法奠定基础。