The aging population is rapidly growing all over the world. Aging is associated with increased susceptibility to chronic lung diseases, especially to chronic obstructive pulmonary disease (COPD). To date there is no cure for COPD, resulting in poor quality of life for patients and a high economic burden. Impairment of lung regeneration and repair is one of the most important steps in COPD progression. Lung regeneration after pneumonectomy is highly induced in lungs of juvenile people; however, aging reduces the regenerative ability of the lungs in humans and experimental animals. Thus, rejuvenation of the lung's intrinsic regenerative ability in aged adults could be a good therapeutic strategy for COPD. Angiogenesis ? the formation of new blood capillaries - plays a key role in organ development and regeneration. Angiogenesis is impaired in aging animals and contributes to COPD progression. Thus, in order to restore regenerative ability in the aged lung, we need to understand the mechanisms by which aging impairs angiogenesis in the lung. The overall goal of this proposal is to characterize the molecular mechanisms governing age-related changes in angiogenesis and how these changes control epithelial morphogenesis in the lung, and to leverage this knowledge to develop efficient strategies for age-related lung diseases such as COPD. The Wnt ligand-receptor complex low-density lipoprotein receptor-related protein 5 (LRP5) controls angiogenesis and lung regeneration. Wnt activity is reduced with aging in the lungs and is involved in cellular senescence and the pathogenesis of COPD. Our new preliminary data demonstrate that expression of LRP5 and angiogenic factor Tie2 is decreased in endothelial cells (ECs) of aged mouse lungs and that knockdown of LRP5 in ECs inhibits EC sprouting and epithelial morphogenesis in vitro. We recently developed a unique method to implant fibrin gel on the mouse lung, which enables the precise analysis of vascular and epithelial morphogenesis in the mouse lung. When we implanted fibrin gel supplemented with fluorescently labeled ECs on the mouse lung, these ECs formed vascular networks and interacted with host-derived alveolar epithelial cells in the gel. We hypothesize that overexpression of LRP5 in ECs stimulates blood vessel formation and epithelial morphogenesis in the aged mouse lung.
In Aim 1, we will isolate ECs from young vs. aged mouse lungs and characterize the age-related changes in angiogenic activity and epithelial morphogenesis in vitro. We will also determine whether LRP5 in ECs mediates the pathway.
In Aim 2, we will implant fibrin gel supplemented with ECs isolated from young vs. aged mouse lungs on the mouse lung and evaluate the effects of EC age on vascular and epithelial morphogenesis in the gel. We will also manipulate LRP5 expression in these ECs and determine the effects on vascular and epithelial morphogenesis in the gel. If this study proves the role of endothelial LRP5 in vascular and alveolar morphogenesis in aged lungs, this work holds considerable promise to lead to the development of new and better strategies for lung regeneration and age-related lung diseases such as COPD.
Understanding the signaling mechanisms that govern age-related changes in angiogenesis is clinically important because angiogenesis plays a key role in lung regeneration and repair, processes that are deregulated in chronic obstructive pulmonary disease (COPD), which afflicts a large number of aging adults, and for which current therapies have not been very successful. The goal of this project is to characterize the molecular mechanisms governing age-related changes in angiogenesis and how these changes contribute to epithelial morphogenesis in the lung using our unique mouse fibrin gel lung implantation system in order to develop efficient strategies for stimulating regeneration in the aged lung. Since low-density lipoprotein receptor-related protein 5 (LRP5) potentially promotes lung regeneration by stimulating angiogenesis in mice and is involved in cellular senescence, if this study proves that manipulation of LRP5 expression in endothelial cells stimulates vascular and epithelial morphogenesis in the aged lung, it holds considerable promise to lead to the development of new and better strategies to stimulate lung regeneration/repair in age-dependent lung diseases such as COPD.
| Mammoto, Akiko; Muyleart, Megan; Kadlec, Andrew et al. (2018) YAP1-TEAD1 signaling controls angiogenesis and mitochondrial biogenesis through PGC1?. Microvasc Res 119:73-83 |
