Respiratory Control in Old Age

老年呼吸控制

• 批准号: 8871511
• 负责人: Carlos B Mantilla
• 金额: $ 40.23万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871511
• 关键词: Accounting; Address; Affinity; Age; Aging; Applications Grants; Area; Atrophic; Behavior; Brain-Derived Neurotrophic Factor; Breathing; Cause of Death; Chest; Chest wall structure; Chronic Disease; Clinical; Contractile Proteins; Contracts; Coughing; Dependovirus; Development; Disease; Elderly; Failure; Fiber; Figs - dietary; Gene Delivery; Generations; Health; Impairment; Incidence; Individual; Infection; Knowledge; Lung; Lung diseases; Mechanics; Motor; Motor Neurons; Muscle; Muscle Contraction; Muscle Fibers; Muscle Weakness; Myosin Heavy Chains; Neuregulin 1; Neuromuscular Diseases; Neuromuscular Junction; Neurotrophic Tyrosine Kinase Receptor Type 2; Operative Surgical Procedures; Phosphotransferases; Pneumonia; Population; Protein Biosynthesis; Proteins; Research; Respiratory Diaphragm; Respiratory Failure; Respiratory Mechanics; Respiratory Muscles; Respiratory System; Respiratory Tract Infections; Respiratory physiology; Rest; Risk; Risk Factors; Role; Sepsis; Serotyping; Signal Transduction; Sneezing; System; Testing; Therapeutic; Time; Tropomyosin; United States; Work; Work of Breathing; age related; human FRAP1 protein; impaired capacity; improved; nerve supply; neuromuscular; neuromuscular transmission; novel; pressure; prevent; protein expression; receptor; respiratory; sarcopenia; therapeutic target; transmission process

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.

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咳嗽和打喷嚏等呼气性非通气行为而导致的。拟议的研究重点关注与老年相关的“完美风暴”状况，我们认为肌少症（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会降低 DIAm 产生力的能力，从而降低跨膈压力（Pdi），同时呼吸系统力学变硬，从而增加 DIAm 必须收缩的负载。 DIAm 必须完成一系列行为，从休息呼吸到咳嗽和打喷嚏等呼出行为。在老年人中，进行排出性、高强度、非通气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，与年龄相关的肌肉减少症和神经肌肉传递衰竭会降低最大 DIAm 力生成能力，从而损害老年人执行涉及气道清除的非通气行为的能力。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）发挥作用，神经调节蛋白-1（NRG-1）通过mTOR激活通过ErbB受体发挥作用，对DIAm神经支配和肌肉减少症的年龄相关变化产生影响。我们假设 BDNF/TrkB 和 NRG-1/ErbB/mTOR 信号传导所产生的营养影响可用于治疗减轻与衰老相关的 DIAm 神经肌肉传递衰竭和肌肉减少症，以及相关的非通气行为损伤。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 信号传导对 DIAm 神经支配年龄相关变化的作用； 3) 确定NRG-1/ErbB/mTOR信号传导在年龄相关的DIAm肌少症中的作用。拟议研究的结果将为老年呼吸系统的变化提供新的基础知识，从而允许开发在呼吸和神经肌肉疾病中广泛应用的新疗法。随着人口老龄化，慢性病发病率上升，需要共同努力改善老年人的健康。