The role of endothelial derived Leucine-Rich Alpha-2-Glycoprotein 1 (LRG1) in the pathogenesis of COPD

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and current therapy only treats symptoms but cannot stop progression of this debilitating disease. COPD is defined as a clinical syndrome characterized by respiratory symptoms, airflow limitation that is irreversible, and pulmonary

structure abnormalities (emphysema and/or airways disease). The key pathologic features of COPD lungs are chronic inflammation, tissue destruction, and vascular abnormalities. Emerging data points to the centrality of the lung microvasculature to the pathogenesis of COPD but little is known of how vascular damage leads to

progressive lung destruction. This proposal addresses the critical need to define the mechanism(s) of vascular pathogenesis of COPD to provide a therapeutic path forward and to reduce the morbidity and mortality for millions of patients with this disease. We have shown that in human COPD lung tissue loss of expression of key

endothelial markers, suggestive of vascular dysfunction, is profound and linked to disease severity. We also found vascular dysfunction in a murine model of emphysema and showed that restoring the pulmonary vascular niche with pulmonary capillary endothelial cell (PCEC) therapy ameliorated emphysema. These data support

the novel concept that the “pulmonary vascular niche” is critical to the integrity of the alveolar-capillary unit, but these results are the first to show that re-establishing the pulmonary endothelial compartment can change the course of the emphysematous state. In PCECs isolated from emphysematous lung, leucine-rich alpha-2-

glycoprotein-1 (Lrg1) was a top up-regulated gene. LRG1, is a secreted glycoprotein that binds to the TGF-𝜷 accessory receptor that in ECs distorts their signaling to cause aberrant blood vessels in several disease states. In this proposal, we hypothesize that excessive levels of PCEC-derived LRG1 alters homeostatic functions of

PCECs leading to a dysregulated vascular niche whereby the development of emphysema ensues. Aim determine employing exposed excessive 3, and to strategies successful Cornell resources 1, will the mechanism(s) by which PCEC LRG1 promotes he pathogenesis of emphysema in mice by the use of genetically modified mice lacking Lrg1 in the adult endothelium. These mice will be

to the cigarette smoke and elastase induced models of emphysema. Aim 2, will define the impact of levels of LRG1 on the alveolar-capillary network in human vascularized lung organoid models. Aim will determine the extent to which perturbations of LRG1 signaling blocks the emphysema phenotype in murine

human model systems using a neutralizing antibody against LRG1. These studies will uncover mechanisms promote normalization of the pulmonary vascular niche o allow alveolar repair and the development of novel to treat COPD. This proposal plays a central role in a career development plan for becoming a

independent investigator focused on vascular dysfunctions in the pathogenesis of COPD. Weill Medicine is an ideal environment in which to execute this training plan because of its rich scientific and the strength of the track record of strong mentorship of early-stage investigators. t t