Loss of progenitor function accelerates lung aging

祖细胞功能丧失加速肺部衰老

基本信息

批准号：
10426410
负责人：
SUSAN M MAJKA
金额：
$ 33.62万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426410
关键词：
5 year old Address Adult Age Aging Attenuated Biological Assay Biology Blood Vessels Cardiovascular system Cell Communication Cell Count Cell physiology Cells Chronic Chronic Obstructive Airway Disease Cigarette smoke-induced emphysema Coculture Techniques Coupled Data Development Disease Distal Dose Endothelium FDA approved Female Functional disorder Goals Histologic Homeostasis Human Immune Impairment In Vitro Inflammation Inflammatory Inflammatory Infiltrate Interleukin-13 Knowledge Link Lung Lung Lavage Fluid Lung diseases Lymphoid Lymphoid Cell Maintenance Medial Mesenchymal Modeling Mus Oxidation-Reduction Pharmaceutical Preparations Phenotype Physiological Physiology Play Predisposition Process Prognosis Proteins Pulmonary Emphysema Stromal Cells Structure Subgroup Testing Tissues Vascular Diseases Vascular remodeling Work aged aging population angiogenesis cell type cytokine epithelial stem cell exhaustion exposure to cigarette smoke human model improved in vivo in vivo evaluation knock-down male mouse model novel premature progenitor pulmonary function sex stem cell function stem cells

项目摘要

Aging is associated with loss of lung structure and declining function, termed senile emphysema. Emphysematous loss of tissue structure is exacerbated by vasculopathy, which substantially worsens prognosis, increases susceptibility to lung disease, and limits survival. We have previously demonstrated that the structure and function of the lung microvasculature is regulated by a specialized mesenchymal vascular progenitor cell (MVPC). We have also defined Dickkopf-related protein 1 (DKK1) as a regulator of this niche in murine and human model. Our preliminary data demonstrate that MVPC numbers decline with age in WT mice by 1 year, and that, when MVPC are depleted in young mice, lung aging is accelerated, resulting in severe emphysema at 1.5 years of age. While MVPC are key modulators of the pulmonary microvasculature in the distal lung, adventitial stem cells (ASC) influence large blood vessel homeostasis in the proximal lung. Our preliminary data identifies key similarities between MVPCs and ASCs suggesting that decline in ASC numbers and function may also result in accelerated lung aging. Given ASC function is tightly controlled by lung-resident type-2 innate lymphoid cells (ILC2) and pulmonary ILC2 are known to decrease with age, loss of ASC-ILC2 crosstalk is likely a contributor to senile emphysema. Our prior work and preliminary data suggest that a novel ILC2 subset serves as a progenitor in repopulating lung-resident ILC2. The goal of this proposal is to define the mechanisms that result in loss of adult MVPC and ILC2 progenitor function contributing to accelerated lung aging and increased susceptibility to emphysema in the aged population. The novel premise of this proposal is that loss of progenitor function accelerates lung aging by altering vascular structure and function. We hypothesize that loss of progenitor function accelerates lung aging by altering cell interactions within vascular niches, promoting vascular remodeling and increasing susceptibility to emphysema in the aging population. We will test that decline in MVPC and ILC2 numbers and/or function in the aging lung accelerates aging via impairment of vascular homeostasis due to disruption of cell – cell interactions in their respective perivascular niches, promoting vascular remodeling and loss of tissue structure using novel conditional murine models to knock down progenitors in aged mice or young mice. We will assess the requirement of MVPC, MVPC derived DKK1, ILC2 cells, and ILC2 derived IL13 in the maintenance of vascular niche homeostasis and susceptibility to emphysema. We will use conditional models to manipulate DKK1 or IL13 expression in mice allowed to age in the presence or absence of cigarette smoke exposure both in vivo and in vitro. Lastly, will test that paquinimod will restore progenitor numbers and function in the lungs of aged mice as well as attenuate cigarette smoke induced emphysema in aged mice. This work will provide an understanding of progenitor aging, mechanisms by which loss of MVPC and ILC2 function drives vascular remodeling contributing to aging and test a strategy to improve progenitor function in the aging population.

衰老与肺结构的丧失和功能下降有关，称为老年肺气肿。血管病会加剧组织结构的杂质损失，这显着恶化预后，增加对肺部疾病的敏感性，并限制了存活率。我们以前已经证明了肺微脉管系统的结构和功能由专门的间充质血管调节祖细胞（MVPC）。我们还将与Dickkopf相关的蛋白1（DKK1）定义为该利基市场的调节剂鼠类和人类模型。我们的初步数据表明，WT小鼠的MVPC数量随着年龄的增长而下降到1年，当MVPC在年轻小鼠中耗尽时，肺老化加速，导致严重 1.5岁的肺气肿。 MVPC是肺微脉管系统的关键调节剂肺远端，外在干细胞（ASC）影响近端肺中的大血管稳态。我们的初步数据标识了MVPC和ASC之间的关键相似性，这表明ASC数量下降功能也可能导致肺老化加速。鉴于ASC功能由肺部居民严格控制已知2型先天淋巴样细胞（ILC2）和肺ILC2随着年龄的增长而降低，ASC-ILC2的丧失 Crosstalk可能是老年肺气肿的贡献者。我们先前的工作和初步数据表明一部小说 ILC2子集充当祖先的祖先，用于肺部居民ILC2。该提议的目的是定义导致成人MVPC和ILC2祖细胞功能损失的机制有助于加速肺老年人口中衰老和对肺气肿的敏感性增加。该提议的新颖前提是祖细胞功能的丧失通过改变血管结构和功能来加速肺老化。我们假设祖细胞功能的丧失通过改变血管中的细胞相互作用来加速肺老化利基市场，促进血管重塑，并增加对衰老人群中肺气肿的敏感性。我们将测试MVPC和ILC2数量的下降和/或功能在衰老的肺中通过由于细胞相互作用的破坏，血管相互作用在其各自的血管周围导致的血管稳态受损利基市场，使用新型的条件鼠模型促进血管重塑和组织结构的损失在老年小鼠或年轻小鼠中击倒祖细胞。我们将评估MVPC，MVPC得出的需求 DKK1，ILC2细胞和ILC2在维持血管生态平衡和易感性方面得出IL13 要肺气肿。我们将使用条件模型来操纵小鼠的DKK1或IL13表达在存在或不存在香烟的情况下，体内和体外都有烟雾。最后，将测试 Paquinimod将恢复老年小鼠肺中的祖细胞数量和功能香烟烟雾引起老年小鼠的肺气肿。这项工作将提供对祖先的理解衰老，MVPC和ILC2功能损失的机制驱动导致衰老的血管重塑并测试一种改善老龄化人群中祖细胞功能的策略。