The reduction of NLRX1 and its role in pulmonary aging

NLRX1的减少及其在肺衰老中的作用

• 批准号: 9324115
• 负责人: Min-Jong Kang
• 金额: $ 34.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324115
• 关键词: Acute Promyelocytic Leukemia; Adenovirus Vector; Adult; Affect; Age; Aging; Aging-Related Process; Alveolar; Americas; Antiviral Agents; Attenuated; Binding; Biological Aging; Biological Response Modifiers; Cell Aging; Characteristics; Chronic Disease; Chronic Obstructive Airway Disease; Cytoprotection; Deterioration; Doxycycline; Elderly; Enterobacteria phage P1 Cre recombinase; Event; Functional disorder; Gene Proteins; Genes; Genetic; Health Care Costs; Homeostasis; Human; Inflammasome; Intervention; Lead; Leucine-Rich Repeat; LoxP-flanked allele; Lung; Mediating; Medicine; Mitochondria; Molecular; Mus; Mutate; Nucleotides; Oral; Organ; PTEN gene; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Phosphotransferases; Physiological; Plant Roots; Play; Population; Production; Proteins; Pulmonary Emphysema; Quality Control; Quality of life; Risk Factors; Role; Signal Transduction; Signaling Molecule; Site; Societies; System; TP53 gene; Testing; Therapeutic; Time; Tissues; Transgenes; Transgenic Organisms; VEGFA gene; aging population; cell type; disability; functional decline; in vivo; macrophage; mitochondrial dysfunction; mutant; normal aging; novel; novel strategies; null mutation; overexpression; restoration

PROJECT SUMMARY Biological aging of the pulmonary system is associated with structural changes that lead to a progressive decline in function, and the term “aging lung” is used to describe the organ in this stage of decline. With population rapidly aging, a thorough understanding of physiologic aging-related changes in the lung is imperative. We recently demonstrated a mitochondrial molecule, nucleotide-binding domain and leucine-rich- repeat-containing protein X1 (NLRX1) which has been identified as a negative regulator of mitochondrial antiviral signaling molecule (MAVS), plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Because aging is a common risk factor for COPD, studies were undertaken to determine if NLRX1 is an important player in “aging lung.” Our preliminary studies revealed that (i) aging itself induced the reduction of NLRX1 at the level of gene and protein in murine lungs; (ii) the site of major reduction was in macrophages; and (iii) the lungs from 12-month-old (mo) NLRX1 null mutant (-/-) mice manifested enhanced characteristics of the “aging lung.” These features observed from NLRX1-/- mice included (a) activation of the inflammasome, (b) increased p53 signaling and its target molecule promyelocytic leukemia (PML; a well-known marker of cellular senescence), (c) decreased production of vascular endothelial growth factor (VEGF), a key regulator of pulmonary vasculature and cytoprotection and (d) enhancement of senile emphysema-like alveolar remodeling, all of which were modestly observed in lungs from wild type (WT) controls. In addition, we identified an unprecedented function of NLRX1 as an interacting molecule with PTEN-induced kinase 1 (PINK1), an essential regulator of mitochondrial quality control. The importance of NLRX1 in aging studies was evident in humans, revealing the expression of NLRX1 was significantly reduced in peripheral blood mononuclear cells from the elderly (age>65) compared to those from young controls (age<40). This constellation of findings led us to hypothesize that aging-induced reduction of NLRX1 plays a critical role in the aging of pulmonary system via, at least, mitochondrial dysfunction/molecular dysregulation. To test the hypothesis, we will utilize newly generated mice in which the NLRX1 gene can be null mutated or induced, respectively, in a temporospatial manner. Proposed aims driven by specific hypotheses are: Aim #1. Define the alteration of NLRX1 and its role(s) in pulmonary aging in vivo; Aim #2. Determine if restoring the expression of NLRX1 in vivo attenuates aging-related alterations in the pulmonary system; Aim #3. Characterize the mitochondrial dysfunction/molecular dysregulation in the lung with aging and define the role that NLRX1 plays in aging-related mitochondrial dysfunction/molecular dysregulation. To our best knowledge, NLRX1, an innate immune regulator, has never been studied in the context of aging. Its specific function(s) in macrophages, in spite of the importance of this cell type for tissue homeostasis with normal aging, have never been defined, either. The proposed aims will explore these unprecedented issues.

项目概要 肺系统的生物老化与导致进行性肺损伤的结构变化有关。 功能衰退，“肺老化”一词就是用来形容这个阶段的器官衰退的。和 人口迅速老龄化，彻底了解与肺部衰老相关的生理变化 至关重要的。我们最近展示了线粒体分子、核苷酸结合域和富含亮氨酸的- 含有重复序列的蛋白 X1 (NLRX1) 已被确定为线粒体的负调节因子 抗病毒信号分子（MAVS）在慢性阻塞性肺疾病的发病机制中发挥着关键作用 疾病（慢性阻塞性肺病）。由于衰老是慢性阻塞性肺病的一个常见危险因素，因此进行了研究以确定是否 NLRX1 是“肺部衰老”的重要参与者。我们的初步研究表明（i）衰老本身会导致 小鼠肺中 NLRX1 在基因和蛋白质水平上的减少； (ii) 主要减少地点位于 巨噬细胞； (iii) 12 个月大 (mo) NLRX1 无效突变 (-/-) 小鼠的肺表现出增强 “肺老化”的特征。从 NLRX1-/- 小鼠观察到的这些特征包括 (a) 炎症小体，(b) p53 信号传导及其靶分子早幼粒细胞白血病 (PML；众所周知的 细胞衰老的标志物），(c) 血管内皮生长因子 (VEGF) 的产生减少，这是一个关键因素 肺血管系统和细胞保护的调节剂以及（d）增强老年性肺气肿样肺​​泡 重塑，所有这些都在野生型（WT）对照的肺部中轻微观察到。此外，我们 确定了 NLRX1 作为与 PTEN 诱导的激酶 1 相互作用的分子的前所未有的功能 (PINK1)，线粒体质量控制的重要调节因子。 NLRX1 在衰老研究中的重要性是 在人类中很明显，揭示外周血中 NLRX1 的表达显着降低 老年人（年龄 > 65 岁）的单核细胞与年轻对照组（年龄 < 40 岁）的单核细胞相比。这 一系列研究结果使我们推测衰老引起的 NLRX1 减少起着关键作用 至少通过线粒体功能障碍/分子失调来影响肺系统的衰老。到 为了检验假设，我们将利用新生成的小鼠，其中 NLRX1 基因可以是无效突变的或 分别以时空方式诱导。由具体假设驱动的拟议目标是： 目标#1。 定义NLRX1的改变及其在体内肺衰老中的作用；目标#2。判断是否恢复 NLRX1 的体内表达可减轻肺系统中与衰老相关的变化；目标#3。 描述随着衰老而出现的肺部线粒体功能障碍/分子失调，并确定其作用 NLRX1 在与衰老相关的线粒体功能障碍/分子失调中发挥作用。据我们所知， NLRX1 是一种先天性免疫调节剂，从未在衰老背景下进行过研究。其具体功能为 尽管巨噬细胞对于正常衰老过程中的组织稳态很重要，但从未被人们所认识到。 也已被定义。拟议的目标将探讨这些前所未有的问题。