Roles for altered Wnt signaling and oxidative stress response pathways as primary drivers of reduced reparative capacity in aging canine lung mesenchymal stromal cells

Wnt信号传导和氧化应激反应途径改变作为衰老犬肺间充质基质细胞修复能力降低的主要驱动因素的作用

• 批准号: 9812355
• 负责人: Julia Adams Paxson
• 金额: $ 39.13万
• 依托单位: COLLEGE OF THE HOLY CROSS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812355
• 关键词: Adult; Aging; Animal Model; Antioxidants; Canis familiaris; Cell Aging; Cell Line; Cell Proliferation; Cell physiology; Cell surface; Chronic; Companions; DNA Damage; DNA Methylation; Data; Development; Disease; Epigenetic Process; Exposure to; Expression Profiling; Funding; Genes; Goals; Human; Lung; Lung Capacity; Lung diseases; Messenger RNA; Metabolic; MicroRNAs; Mission; Modeling; Mus; Oxidative Regulation; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Post-Transcriptional Regulation; Predisposition; Production; Progressive Disease; Public Health; Pulmonary Pathology; Regulation; Research; Role; Science; Signal Pathway; Study models; System; Testing; Tissues; United States National Institutes of Health; WNT Signaling Pathway; Work; age related; aged; base; beta catenin; biological adaptation to stress; design; effective therapy; epigenetic regulation; functional decline; human disease; lung repair; mesenchymal stromal cell; methylation pattern; novel; overexpression; promoter; pulmonary function decline; response; superoxide dismutase 1; theories; tissue repair; undergraduate student

Project Summary An emerging paradigm postulates that cellular aging is driven by epigenetic alterations of developmental signaling pathways. Alternative theories suggest that dysregulation of the oxidative stress response, DNA damage accumulation, global epigenetic drift, or metabolic byproduct accumulation are more important. Our inability to identify the primary drivers of cellular aging highlights a critical gap in our ability to design effective ways to treat and reverse age-related disease pathologies. Aging in humans is associated with reduced tissue repair, declining pulmonary function, and an enhanced susceptibility to chronic pulmonary diseases that are progressive, destructive and irreversible. Our overall objective in this proposed work is to identify the primary drivers of age-related functional decline in highly proliferative multipotent lung mesenchymal stromal cells (LMSCs). Like other tissue resident MSCs, LMSCs are tightly regulated, critical in development and adult tissue repair, and sensitive to age-related dysregulation. We have previously demonstrated that aging mice have reduced lung repair capacity and reduced LMSC function. Our proposed work will identify drivers of LMSC aging in companion dogs, a novel naturally-aging model in which we can identify broadly conserved mechanisms relevant to human aging. Our central hypothesis is that epigenetically-regulated changes in Wnt signaling and oxidative stress response pathways are interdependent primary drivers of reduced reparative function in aging LMSCs. This central hypothesis is based on our preliminary data showing that aLMSCs (isolated from aged dogs) have lower clonogenicity and proliferation, altered expression profiles of Wnt signaling components and oxidative response genes, and altered adaptive response to oxidative stress compared to yLMSCs (isolated from young dogs). We will test our central hypothesis by pursuing the following two specific aims. Aim 1. Identify how regulation of Wnt signaling drives the age-related decrease in reparative capacity of LMSCs. From our preliminary data, our working hypothesis is that epigenetic changes in Wnt signaling drive reduced reparative capacity in aLMSCs versus yLMSCs. Aim 2. Identify regulatory drivers of the cellular response to oxidative stress in aged LMSCs. From our preliminary data, our working hypothesis is that epigenetic changes in key adaptive oxidative stress response genes leads to a dysregulated oxidative response and reduced reparative capacity in aLMSCs versus yLMSCs. Our rationale is that we will identify conserved drivers of age-related functional decline in MSCs that will be critical for understanding the pathogenesis of age-related diseases in human patients.

项目摘要 一个新兴的范式假设细胞衰老是由表观遗传改变驱动的， 发育信号通路。替代理论认为， 氧化应激反应、DNA损伤累积、整体表观遗传漂移或代谢 副产物积累更为重要。我们无法确定 细胞老化凸显了我们设计有效治疗和逆转癌症的方法的能力的关键差距。 与年龄相关的疾病病理学。人类的衰老与组织修复减少有关， 肺功能下降，对慢性肺部疾病的易感性增加 是渐进的、破坏性的和不可逆转的。我们这项拟议工作的总体目标是 确定高度增殖性多能干细胞中年龄相关性功能下降的主要驱动因素， 肺间充质基质细胞（LMSCs）。与其他组织驻留MSC一样，LMSC紧密地 调节，在发育和成人组织修复中至关重要，并且对年龄相关的 失调我们之前已经证明，衰老的小鼠减少了肺修复， 容量和减少的LMSC功能。我们建议的工作将确定LMSC老化的驱动因素， 伴侣狗，一种新的自然衰老模型，我们可以识别广泛保守的 与人类衰老有关的机制。我们的中心假设是， Wnt信号传导和氧化应激反应途径的变化是相互依赖的主要 老化LMSC修复功能降低的驱动因素。这个核心假设是基于我们的 初步数据显示aLMSC（分离自老年狗）具有较低的克隆形成性， 增殖、Wnt信号传导组分的表达谱改变和氧化反应 基因，并与yLMSC（分离自 幼犬）。我们将通过追求以下两个具体目标来检验我们的中心假设。 目标1.确定Wnt信号传导的调节如何驱动与年龄相关的修复性降低 LMSC的能力。从我们的初步数据来看，我们的工作假设是 Wnt信号传导的变化驱动aLMSC相对于yLMSC的修复能力降低。目标2. 确定老化LMSC中细胞对氧化应激反应的调控驱动因素。从我们 初步数据，我们的工作假设是，表观遗传变化的关键适应性氧化 应激反应基因导致氧化反应失调， aLMSC与yLMSC的容量。我们的理由是，我们将确定保守的驱动程序， 年龄相关的MSC功能下降，这将是至关重要的了解发病机制， 与年龄有关的疾病。