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：
10579157
负责人：
SUSAN M MAJKA
金额：
$ 69.86万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579157
关键词：
5 year old Acceleration Address Adult Age Aging Biological Assay Biology Blood Vessels Cardiovascular system Cell Communication Cell Count Cell physiology Cells Cellular Structures Characteristics Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Coculture Techniques Coupled Data Development Disease Distal Endothelium 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 Patients Phenotype Physiological Physiology Plasma Play Population Predisposition Process Prognosis Proteins Pulmonary Emphysema Sampling Senility Smoker Smoking Stromal Cells Structure Structure of parenchyma of lung Subgroup Testing Tissues Vascular Diseases Vascular remodeling Work aged aging population angiogenesis cytokine epithelial stem cell exhaustion exposure to cigarette smoke human model immune cell infiltrate in vivo in vivo evaluation knock-down male mouse model novel premature progenitor pulmonary function stem cell function stem cells transcriptomics

项目摘要

Aging is associated with loss of lung structure and declining function. Emphysematous loss of tissue structure is exacerbated by vasculopathy, which 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 emphysema. Similar to aging, vascular remodeling is driven by chronic activation of type 2 (Th2) inflammation. Our preliminary data support increased Th2 cytokine profiles in plasma and BAL of COPD patients. Human and murine scRNAseq data define ILC2 and MVPC populations as well as immune cell infiltrate and cytokine expression characteristic of Th2 inflammation in COPD and a smoking model. 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, by altering vascular structure and function, and increased susceptibility to emphysema in the aged population. 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, we will test that loss of ILC2 and MVPC progenitors promotes lung aging and is associated with COPD and a type-2 immune endotype. This work will provide an understanding of progenitor aging, mechanisms by which loss of MVPC and ILC2 function drives vascular remodeling with a Th2 endotype contributing to lung aging and emphysema.

衰老与肺结构丧失和组织结构功能下降有关。血管病变会加剧这种情况，从而增加对肺部疾病的易感性，并限制生存。先前证明肺微血管的结构和功能受我们还定义了 Dickkopf 相关蛋白。 1 (DKK1) 作为小鼠和人类模型中这一生态位的调节剂，我们的初步数据表明。 WT 小鼠中 MVPC 数量随着年龄的增长而下降 1 岁，并且当年轻小鼠中 MVPC 耗尽时，肺部老化加速，导致 1.5 岁时出现严重肺气肿，而 MVPC 是关键调节剂。远端肺的肺微血管的外膜干细胞（ASC）影响大血管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 数量和功能的下降也可能导致肺部加速老化。功能受到肺驻留 2 型先天淋巴细胞 (ILC2) 的严格控制，肺 ILC2 已知随着年龄的增长，ASC-ILC2 串扰的丧失可能与衰老类似，导致肺气肿。血管重塑是由 2 型 (Th2) 炎症的慢性激活驱动的。我们的初步数据支持。人类和小鼠 scRNAseq 数据中 COPD 患者血浆和 BAL 中的 Th2 细胞因子谱增加。定义 ILC2 和 MVPC 群体以及免疫细胞浸润和细胞因子表达特征 COPD 中的 Th2 炎症和吸烟模型该提案的目标是定义其机制。导致成人 MVPC 和 ILC2 祖细胞功能丧失，从而加速肺衰老，通过改变血管结构和功能，以及老年人群对肺气肿的易感性增加。通过改变血管内的细胞相互作用，促进祖细胞功能的丧失，加速肺部衰老利基，促进血管重塑并增加老年人对肺气肿的易感性。将测试衰老肺部中 MVPC 和 ILC2 数量和/或功能的下降是否会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破坏而导致血管稳态受损使用新型条件小鼠模型促进血管重塑和组织结构丧失我们将评估 MVPC、MVPC 衍生的需求。 DKK1、ILC2 细胞和 ILC2 衍生的 IL13 在维持血管生态位稳态和易感性中的作用我们将使用条件模型来操纵衰老小鼠中的 DKK1 或 IL13 表达。最后，我们将在体内和体外测试是否存在香烟烟雾暴露。 ILC2 和 MVPC 祖细胞促进肺衰老，并与 COPD 和 2 型免疫相关这项工作将提供对祖细胞衰老以及 MVC 丧失的机制的了解。 ILC2 功能通过 Th2 内型驱动血管重塑，导致肺衰老和肺气肿。