Respiratory Control in Old Age

描述(由申请人提供)：有大量证据表明，老年与呼吸道并发症的发生率增加有关，这些并发症是由于无法进行咳嗽和打喷嚏等非通气性行为而导致的。建议的研究集中在与老年有关的“完美风暴”状态，我们认为，石棺减少(横隔肌(DIAM)纤维萎缩和比力降低)与增加的神经肌肉传递故障一起降低了DIAM产生力量的能力，从而降低了跨横隔膜压力(PDI)，同时呼吸系统机械结构变得僵硬，从而增加了DIAM必须收缩的负荷。DIAM必须完成一系列行为，从休息呼吸到咳嗽和打喷嚏等排出行为。在老年人中，执行驱逐性、高强度、非呼吸性行为的能力缺陷可能会增加感染和呼吸衰竭的风险。我们的工作假设是，与年龄相关的石棺减少和神经肌肉传递障碍降低了最大直径力量产生能力，损害了老年人执行涉及呼吸道清除的非通气性行为的能力。这项拟议的研究将确定脑源性神经营养因子(BDNF)通过原肌球蛋白相关激酶受体(TrkB)和神经调节蛋白-1(NRG-1)通过ErbB受体通过mTOR激活对Diam神经支配和骨骼肌减少的年龄相关变化所产生的营养影响的作用。我们推测，BDNF/TrkB和NRG-1/ErbB/mTOR信号的营养影响可用于治疗减轻衰老相关的DIAM神经肌肉传递失败和肌萎缩症，以及相关的非通气性行为的损害。我们提出了以下三个具体目标来解决这些假说：1)确定老年对呼吸力学的功能影响；2)确定BDNF/TrkB信号在与年龄相关的DiAM神经支配变化中的作用；3)确定NRG-1/ErbB/mTOR信号在老年性Diam肌无力中的作用。拟议的研究结果将提供有关老年呼吸系统变化的新的基础知识，从而使开发广泛应用于呼吸系统和神经肌肉疾病的新疗法成为可能。随着人口老龄化，慢性病的发病率越来越高，需要共同努力改善老年人的健康。

DESCRIPTION (provided by applicant): There is substantial evidence that old age is associated with an increased incidence of respiratory complications that result from an inability to perform expulsive non-ventilatory behaviors such as coughing and sneezing. The proposed studies focus on the "perfect storm" condition related to old age, where we believe that sarcopenia (diaphragm muscle (DIAm) fiber atrophy and decreased specific force) together with increased neuromuscular transmission failure reduce the ability of the DIAm to generate force, and thus transdiaphragmatic pressure (Pdi), while at the same time the respiratory system mechanics are stiffening thereby increasing the load against which the DIAm must contract. The DIAm must accomplish a range of behaviors from resting breathing to expulsive behaviors such as coughing and sneezing. In the elderly, a deficit in the ability to perform expulsive, high-intensity, non-ventilatory behaviors likely contributes to increased risk for infections and respiratory failure. Our working hypothesis is that age-related sarcopenia and neuromuscular transmission failure reduce maximum DIAm force-generating capacity, impairing the ability of the elderly to perform non-ventilatory behaviors involved in airway clearance. The proposed research will determine the role of trophic influences exerted by brain-derived neurotrophic factor (BDNF) acting through tropomyosin related kinase receptor (TrkB) and neuregulin-1 (NRG-1) acting through ErbB receptors via mTOR activation on the age-related changes in DIAm innervation and sarcopenia. We hypothesize that trophic influences exerted by BDNF/TrkB and NRG-1/ErbB/mTOR signaling can be used therapeutically to mitigate aging-related DIAm neuromuscular transmission failure and sarcopenia, and the associated impairment of non-ventilatory behaviors. We propose the following three specific aims to address these hypotheses: 1) To determine the functional impact of old age on respiratory mechanics; 2) To determine the role of BDNF/TrkB signaling on the age-related changes in DIAm innervation; and 3) To determine the role of NRG-1/ErbB/mTOR signaling in age- related DIAm sarcopenia. The results of the proposed studies will provide new and fundamental knowledge of changes in the respiratory system in old age, and thus permit the development of novel therapies with broad application in respiratory and neuromuscular diseases. The greater incidence of chronic diseases associated with the aging of our population demands concerted efforts to improve the wellness of the elderly.