Respiratory Control in Old Age

老年呼吸控制

• 批准号: 8665855
• 负责人: Carlos B Mantilla
• 金额: $ 41.48万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665855
• 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; 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; public health relevance; 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，老年与呼吸并发症发生率的增加有关，呼吸并发症的发生率增加是由于无法执行诸如咳嗽和打喷嚏等驱逐性的非通知行为而导致的。拟议的研究集中于与老年有关的“完美风暴”状况，我们认为肌肉减少症（diaphragm肌肉（直径）纤维萎缩和降低了特定的力），以及增加神经肌肉的传播故障降低了直径的能力，从而减少了产生力的能力，从而在同一时间内降低了型号的压力（PDI），使得轴向均应增加了系统机制，使该系统的变化是在加工的。直径必须达到从休息呼吸到咳嗽和打喷嚏等驱逐行为的一系列行为。在老年人中，执行驱逐性，高强度，非通知行为的能力不足可能导致感染和呼吸衰竭的风险增加。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播失败降低了最大的直径力产生能力，从而损害了老年人执行与气道通关有关的非通风行为的能力。 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.我们假设BDNF/TRKB和NRG-1/ERBB/MTOR信号施加的营养影响可以通过治疗方法来减轻与衰老相关的DIAM神经肌肉传播失败和肌肉减少症，以及与非发病性行为的相关障碍。我们提出以下三个特定旨在解决这些假设的特定旨在：1）确定老年对呼吸技工的功能影响； 2）确定BDNF/TRKB信号传导在与年龄相关的直径变化中的作用； 3）确定NRG-1/ERBB/MTOR信号传导在与年龄相关的DIAM肌肉减少症中的作用。拟议研究的结果将为老年呼吸系统变化提供新的和基本的知识，从而允许开发具有广泛应用在呼吸和神经肌肉疾病中的新型疗法。与我们人口老龄化有关的慢性疾病的发生率更大，需要协同努力来改善老年人的健康。