Loss of progenitor function accelerates lung aging

祖细胞功能丧失加速肺部衰老

• 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
• 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

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.

衰老与肺结构丧失和功能下降有关，称为老年性肺气肿。 血管病变会加剧肺气肿组织结构的丧失，血管病变实质上会恶化。 预后，增加肺部疾病的易感性，并限制生存。我们之前已经证明过 肺微血管的结构和功能由一种特殊的间充质血管调节。 祖细胞(MVPC)。我们还将Dickkopf相关蛋白1(Dkk1)定义为该利基的调节因子 小鼠和人类模型。我们的初步数据显示，WT小鼠的MVPC数量随着年龄的增长而下降 到1岁时，当幼年小鼠的MVPC耗尽时，肺衰老加速，导致严重的 1.5岁时患肺气肿。而MVPC是肺微血管系统的关键调节器 远端肺、外膜干细胞(ASC)影响近端肺大血管的动态平衡。我们的 初步数据确定了MVPC和ASC之间的关键相似之处，表明ASC数量下降 而功能也可能导致肺老化加速。特定的ASC功能由肺部居住者严密控制 已知2型固有淋巴样细胞(ILC2)和肺ILC2随着年龄的增长而减少，ASC-ILC2的缺失 相声很可能是老年性肺气肿的原因之一。我们之前的工作和初步数据表明，一部小说 ILC2亚群在肺居留ILC2的再生过程中起着祖细胞的作用。这项提案的目标是界定 成人MVPC和ILC2祖细胞功能丧失导致肺加速的机制 老龄化和老年人口对肺气肿的易感性增加。这项提议的新前提是 先祖功能的丧失会通过改变血管结构和功能来加速肺衰老。我们 假设祖细胞功能丧失通过改变血管内细胞相互作用加速肺衰老 利基，促进血管重塑和增加老年人口中患肺气肿的易感性。我们 将测试老化肺中MVPC和ILC2数量和/或功能的下降通过以下方式加速衰老 由于各自血管周围细胞间相互作用的中断而导致的血管内稳态受损 利基，促进血管重塑和组织结构丢失使用新的条件小鼠模型 击倒老年小鼠或年轻小鼠的祖细胞。我们将评估MVPC的需求，MVPC派生 Dkk1、ILC2细胞和ILC2来源的IL13在维持血管生态位稳态和敏感性中的作用 致肺气肿。我们将使用条件模型来操纵Dkk1或IL13在允许衰老的小鼠中的表达 在体内和体外有或没有香烟烟雾暴露的情况下。最后，我将测试一下 帕奎莫特能恢复衰老小鼠肺内祖细胞的数量和功能，并使其减毒 香烟烟雾致老龄小鼠肺气肿。这项工作将提供对先辈的理解 衰老，MVPC和ILC2功能丧失导致血管重构导致衰老的机制 并测试在老龄化人口中改善祖细胞功能的策略。