Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema - 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.
