Systems Based Analysis of Host Factors that Contribute to Aging Pathogenesis

 描述(申请人提供)：病毒性呼吸道感染是美国和世界范围内住院、经济损失和死亡的主要原因之一。随着新出现的病原体以及更常见的呼吸道病毒并发症的持续威胁，了解这些感染及其伴随的宿主反应仍然是全球公共卫生的主要优先事项。特别是，还必须努力在人口老龄化的背景下理解这些感染。虽然现代细菌理论大大减轻了它的负担，但传染病仍然是导致老年人死亡的第四大原因。再加上未来20年老龄人口的强劲增长，这些因素突显了了解感染和衰老宿主之间相互作用的重要性。虽然在了解与年龄相关的获得性免疫缺陷方面已经取得了重大进展，但对衰老宿主中组织特异性和先天免疫细胞功能的了解却很少。因此，这些研究采用了一种基于系统的方法来表征和检查衰老背景下对呼吸道病毒感染的早期组织特异性和先天免疫反应。利用严重急性呼吸综合征冠状病毒(SARS-CoV)，该提案试图比较年轻、中年和老年小鼠，以识别、确认和验证有助于增强易感性并可用于治疗的途径和免疫激活的重大变化。此外，该项目还将检查扩展到原代人类呼吸道和免疫细胞，以确认和验证体内的发现。最后，将努力探索广泛的表观遗传变化对青年和老年模型差异反应的贡献。总而言之，这些方法将产生重要的发现，对了解和治疗老年人口当前和未来的呼吸道病毒感染至关重要。

 DESCRIPTION (provided by applicant): Viral respiratory tract infections are among the leading causes of hospitalization, economic loss, and mortality in the US and worldwide. With the continued threat from emerging pathogens as well as complications from more common respiratory viruses, understanding these infections and their accompanying host responses remain a major priority for global public health. In particular, efforts must also be made to understand these infections within the context of an aging population. While modern germ theory has greatly reduced its burden, infectious disease remains the fourth leading cause of death in aging adults. Coupled with the robust increase in aged populations over the next two decades, these factors highlight the importance of understanding the interplay between infection and the senescent host. While significant progress has been made in understanding the age-related deficiency in adaptive immunity, much less is understood about tissue specific and innate immune cell function in the aging host. Therefore, these studies take a systems based approach to characterize and examine the early tissue-specific and innate immune responses to respiratory virus infection within the context of aging. Utilizing severe acute respiratory syndrome coronavirus (SARS-CoV), the proposal seeks to compare young, middle-aged, and aged mice in order to identify, confirm, and validate major change in pathway and immune activation that contribute to enhanced susceptibility and can be exploited for therapeutic treatment. In addition, the project extends examination into primary human airway and immune cells in order to confirm and validate in vivo finding. Finally, efforts will be made to explore th contribution of broad epigenetic changes to differential responses in young and aged models. Together, these approaches will yield important findings critical to understanding and treating current and future respiratory virus infections in aged populations.