Respiratory Control in Old Age

描述（由申请人提供）：有大量证据表明，老年与呼吸系统并发症的发生率增加有关，这些并发症是由于无法进行排气性非通气行为（如咳嗽和打喷嚏）而引起的。我们提出的研究集中在与老年相关的“完美风暴”条件下，我们认为肌肉减少症（膈肌（DIAm）纤维萎缩和比力下降）以及神经肌肉传递失败的增加降低了膈肌产生力的能力，从而降低了横膈膜压力（Pdi），同时呼吸系统力学变硬，从而增加了膈肌必须收缩的负荷。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性行为。在老年人中，缺乏排气量、高强度、非通气行为的能力可能会增加感染和呼吸衰竭的风险。我们的工作假设是，与年龄相关的肌肉减少症和神经肌肉传递失败降低了DIAm的最大发力能力，损害了老年人进行气道清除等非通气行为的能力。该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mTOR激活通过ErbB受体发挥的营养影响在DIAm神经支配和肌肉减少症的年龄相关变化中的作用。我们假设BDNF/TrkB和NRG-1/ErbB/mTOR信号所施加的营养影响可以用于治疗，以减轻衰老相关的DIAm神经肌肉传递失败和肌肉减少症，以及相关的非通气行为损害。我们提出以下三个具体目标来解决这些假设：1)确定老年对呼吸力学的功能影响；2)确定BDNF/TrkB信号在年龄相关性DIAm神经支配变化中的作用；3)确定NRG-1/ErbB/mTOR信号在年龄相关性DIAm肌少症中的作用。这些研究的结果将为老年呼吸系统的变化提供新的和基础的知识，从而允许开发具有广泛应用于呼吸和神经肌肉疾病的新疗法。与人口老龄化有关的慢性病发病率增加，要求我们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.