Respiratory Control in Old Age

到2030年，美国约有7000万人将超过65岁，约有1000万人超过85岁。 老了本竞争性更新申请中提出的研究的动机是我们的 先前的研究发现，较大的膈运动神经元（PhMN）在老年人中选择性丢失， 年龄和其他人的工作暗示运动神经元死亡的线粒体破坏。 BDNF/TrkB信号转导介导CREB在丝氨酸133（pCREBs 133）的磷酸化， 通过PGC 1a基因靶向促进线粒体重塑。活动依赖性 pAMPK信号还介导pCREBs 133磷酸化和PGC 1a表达。它 PhMNs中的BDNF/TrkB信号在老年时减少，但在老年时， PhMN坚持支持呼吸，这可能是他们在老年时节省的基础。是 循环中的TNF α随着年龄的增长而升高。在其他细胞类型中，我们 发现TNF α选择性激活IRE 1a/sXBP 1 ER应激通路， 诱导线粒体碎裂和线粒体自噬。我们的实验设计包括 我们实验室已经建立并验证了一系列全面的新技术。 拟议研究的结果将指导新的治疗药物的开发。 靶向BDNF/TrkB或pCREB 133磷酸化的方法（例如，槲皮素）和/或 TNF α诱导的IRE 1 a/sXBP 1 ER应激（例如，英夫利昔单抗）以促进PhMN存活。 概念框架：我们假设线粒体体积密度（MVD）和 PhMN中的呼吸能力（SDHmax）受以下平衡的影响： 线粒体生物发生和线粒体自噬。线粒体的生物合成是通过 pCREBs 133磷酸化和PGC 1a表达，这是由两种活性触发的 (via pAMPK-Aim 1）和BDNF/TrkB.FL信号传导（Aim 2）。到了老年， BDNF/TrkB.FL信号转导减少，尤其是在较大的PhMN中，而BDNF/TrkB.FL信号转导的活性降低， 较小的PhMN仍然存在。此外，血清TNF α在老年时升高，这诱导了 pIRE 1a/sXBP 1 ER应激导致线粒体自噬（Aim 3）。 目的1：确定pAMPK/pCREB/PGC 1a信号通路在维持细胞凋亡中的作用。 较小PhMN中的线粒体体积密度。 目的2：确定BDNF/TrkB/pCREB信号转导减少对年龄相关性脑梗死的影响。 PhMN中线粒体的重塑。 目的3：确定TNF α诱导的IRE 1a/sXBP 1 ER应激激活的影响 在PhMN中与年龄相关的线粒体重塑途径。

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.