Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema

这项研究计划的总体任务是定义肺间充质血管 祖细胞枯竭促进肺老化和对肺气肿的易感性。上皮祖细胞丢失 功能是加速肺老化和肺气肿发展的统一因素。然而，同样作为 重要但知之甚少的是，我们对间充质血管前体细胞的理解存在差距 (MVPC)在这些过程中。这项提议意义重大，因为它试图填补一些重要的空白 围绕MVPC祖细胞群体功能障碍如何导致衰老和增加 通过调节血管重塑和血管稳定丧失对肺气肿的易感性。对MVPC的分析 -肺生态位相互作用提供了靶向丰富的环境，以识别MVPC祖细胞依赖的细微差别 与血管停滞、衰老和肺气肿的病理生物学相关的途径，以及识别 恢复组织功能的治疗学。基于互补性，我们提出了三个重点研究领域 主题。主题1健康和老年肺中MVPC功能的调节：我们将利用我们独特的体内和体内 识别MVPC功能和适应性血管生成如何在组织中调节的体外模型系统 动态平衡和衰老。主题2健康、老年和吸烟人群中MVPC功能丧失的后果 暴露的肺：我们将展示MVPC功能的丧失，由于耗尽或信号改变，导致血管病变 以及随后的肺老化和肺气肿。主题3老年患者MVPC功能的治疗性抢救 香烟烟雾暴露肺：我们将验证MVPC的使用和FDA批准的帕奎莫特的再利用 以恢复MVPC的数量和功能，随后的组织功能，并建立干预的时间框架。 这些研究的积极结果很容易翻译。我们将利用我们在National的强大合作 犹太人、科罗拉多大学以及国际公认的合作者提供基本和 单细胞MVPC功能和分化调控机制的翻译理解 以及它们如何调节它们的利基和肺微环境。我们还将定义祖先是否 采用MVPC细胞治疗或介入治疗抢救，可恢复肺结构和功能。

The overall mission of this research program is to define how pulmonary Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema. Loss of epithelial progenitor cell function is a unifying factor in accelerated lung aging, and the development of emphysema. However, equally as important but poorly understood, there is a gap in our understanding of mesenchymal vascular progenitors (MVPC) in these processes. This proposal is significant as it attempts to fill in a number of important gaps surrounding how dysfunction of the MVPC progenitor population, contributes to aging and increased susceptibility to emphysema via regulation of vascular remodeling and loss of angiostasis. Analysis of the MVPC - lung niche interactions provide a target rich environment to identify nuances in MVPC progenitor dependent pathways relevant to the pathobiology of Angiostasis, Aging and Emphysema, as well as the potential to identify therapeutics to restore tissue function. We propose three focus areas for our research based on complementary themes. Theme 1 Regulation of MVPC function in healthy and aged lung: we will use our unique in vivo and in vitro model systems to identify how MVPC function and adaptive angiogenesis is regulated during tissue homeostasis and aging. Theme 2 Consequence of MVPC Loss of Function in healthy, aged and cigarette smoke exposed lung: we will show that loss of MVPC function, by depletion or altered signaling, drives vasculopathy and subsequent lung aging and emphysema. Theme 3 Therapeutic Rescue of MVPC function in aged and cigarette smoke exposed lung: we will validate the use of MVPC and repurposing of FDA approved paquinimod to restore MVPC numbers and function, subsequent tissue function and establish time frames for intervention. Positive results from these studies are readily translatable. We will leverage our strong collaborations, at National Jewish, University of Colorado as well as internationally recognized collaborators provide a basic and translational understanding of the mechanisms regulating MVPC function and differentiation at the single cell level as well as how they regulate their niche and lung microenvironment. We will also define whether progenitor rescue with MVPC cell therapy or interventional treatment will restore lung structure and function.