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Respiratory Control in Old Age

老年呼吸控制

基本信息

批准号：
10740986
负责人：
Carlos B Mantilla
金额：
$ 61.53万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740986
关键词：
Affect Age Years Aging Amyotrophic Lateral Sclerosis Atrophic Behavior Biogenesis Brain-Derived Neurotrophic Factor Breathing CDC2 gene CREB1 gene Chronic Disease Coughing Denervation Development Elderly Equilibrium Experimental Designs Fiber Gene Expression Gene Targeting Impairment Incidence Intervention Link Mediating Mitochondria Modeling Motor Neurons Muscle Muscle Fibers Muscle Weakness Muscular Atrophy PINK1 gene Parkin Pathway interactions Performance Persons Phosphorylation Population Predisposition Quercetin Rattus Research Respiratory Diaphragm Respiratory Tract Infections Risk Role Serine Serum Signal Transduction Sneezing Techniques Work age related age-related muscle loss cell type cytokine density endoplasmic reticulum stress human old age (65+)human very old age (85+)infliximab injured airway mitochondrial dysfunction mortality motor neuron degeneration neuron loss neuronal survival novel novel therapeutic intervention novel therapeutics protective behavior protein expression respiratory sarcopenia

项目摘要

By 2030, ~70 million people in the USA will be >65 years old with ~10 million >85 years old. The studies proposed in this competitive renewal application are motivated by our previous finding that larger phrenic motor neurons (PhMNs) are selectively lost in old age and the work of others implicating mitochondrial disruption in motor neuron death. BDNF/TrkB signaling mediates CREB phosphorylation at serine 133 (pCREBs133), which promotes mitochondrial remodeling via gene targeting of PGC1a. Activity dependent pAMPK signaling also mediates pCREBs133 phosphorylation and PGC1a expression. It appears that BDNF/TrkB signaling in PhMNs is reduced in old age, but activity of smaller PhMNs persists to support breathing, which may underlie their sparing in old age. It is also well established that circulating TNFa is elevated with aging. In other cell types, we found that TNFa selectively activates the IRE1a/sXBP1 ER stress pathway, which induces mitochondrial fragmentation and mitophagy. Our experimental design involves a comprehensive array of novel techniques already established and validated in our lab. The results of the proposed studies will guide development of novel therapeutic approaches targeting BDNF/TrkB or pCREBs133 phosphorylation (e.g., quercetin) and/or TNFa induced IRE1a/sXBP1 ER stress (e.g., infliximab) to promote PhMN survival. Conceptual Framework: We hypothesize that mitochondrial volume density (MVD) and respiratory capacity (SDHmax) in PhMNs are affected by the balance between mitochondrial biogenesis and mitophagy. Mitochondrial biogenesis is regulated via pCREBs133 phosphorylation and PGC1a expression, which is triggered by both activity (via pAMPK – Aim 1) and BDNF/TrkB.FL signaling (Aim 2). In old age, the influence of BDNF/TrkB.FL signaling is diminished especially in larger PhMNs, while activity of smaller PhMNs persists. Furthermore, serum TNFa is elevated in old age, which induces pIRE1a/sXBP1 ER stress leading to mitophagy (Aim 3). Aim 1: Determine the role of pAMPK/pCREB/PGC1a signaling in maintaining mitochondrial volume density in smaller PhMNs.. Aim 2: Determine the impact of reduced BDNF/TrkB/pCREB signaling in age-related remodeling of mitochondria in PhMNs. Aim 3: Determine the impact of TNFa induced activation of the IRE1a/sXBP1 ER stress pathway in age-related remodeling of mitochondria in PhMNs.

到2030年，美国65岁以上的人口将达到7000万，85岁以上的人口将达到1000万

项目成果

期刊论文数量（64）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of TrkB kinase activity impairs transdiaphragmatic pressure generation.

抑制 TrkB 激酶活性会损害跨膈压力的产生。

DOI：
10.1152/japplphysiol.00564.2019
发表时间：
2020
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
0
作者：
Pareja-Cajiao,Miguel;Gransee,HeatherM;Cole,NaomiA;Sieck,GaryC;Mantilla,CarlosB
通讯作者：
Mantilla,CarlosB

Diaphragm muscle sarcopenia into very old age in mice.

小鼠膈肌肌少症一直持续到很高龄。

DOI：
10.14814/phy2.14305
发表时间：
2020
期刊：
Physiological reports
影响因子：
2.5
作者：
Vang,Pangdra;Vasdev,Amrit;Zhan,Wen-Zhi;Gransee,HeatherM;Sieck,GaryC;Mantilla,CarlosB
通讯作者：
Mantilla,CarlosB

Muscle weakness in critical illness.

危重疾病时肌肉无力。