Idiopathic pulmonary fibrosis is an incurable condition characterized by the progressive accumulation of scar tissue in the adult human lung. It typically leads to death within approximately three years of diagnosis and while several pharmacologic agents have shown some benefit in delaying disease progression, the effects of these interventions are limited, heterogeneous, and accompanied by toxicity. Thus, further investigation of the mechanisms driving fibrotic responses remains an important area of study. Current paradigms of pulmonary fibrosis propose this process to result from a mismatch between epithelial cell injury and excessive fibroblast repair responses that may be amplified by abnormalities in macrophage phenotypes. Understanding all of these aspects of fibrosis is of particular importance in IPF, where patients present with established and often progressive disease. The study of neuronal guidance proteins is an emerging area in the field of tissue injury and repair. Our laboratory was the first to study this class of proteins in the context of human lung disease when we defined the association of the GPI-anchored membrane protein Semaphorin 7a with IPF. In the nervous system, Sema 7a regulates neuronal growth via the competing effects of ?1?1 integrin and the transmembrane protein Plexin C1. We have shown this mechanism to be active in several forms of mammalian lung fibrosis and inflammation where Sema 7a's stimulatory effects are enacted via an integrin-mediated process that is opposed by Plexin C1. Our additional work in this area indicates a novel role for the laminin-like protein Netrin-1 in the integrin-mediated processes. Netrin-1 (NTN-1), a secreted neuronal guidance protein, stimulates cellular attraction via binding to its attractive receptor, Deleted in Colorectal Cancer-1 (DCC-1) while cellular repulsion and invasion is driven by interactions with its repulsive receptor, Uncoordinated-5a (UNC5a). In contrast, Plexin C1 (PLXNC1) inhibits Sema 7a-driven processes via two pathways; namely, the inactivation of the Harvey rat sarcoma oncogene, Rras, and the modulation of cellular function via the phosphorylation of the Lim kinase-2 (LimK2). Published and preliminary work by members of our group in this and other diseases indicate that the Netrin-1's stimulatory components are excessively activated in IPF and in several experimental models of pulmonary fibrosis, whereas PLXNC1's protective functions are suppressed. The mechanisms and potential therapeutic benefit to IPF remain undefined. This grant proposes a translational approach combining state of the art mass cytometry based analysis of primary human biospecimens, novel bioengineering based ex vivo models, and sophisticated murine modeling to evaluate this hypothesis.
In aim 1 we will determine the site of expression of NTN-1 and PLXNC1 pathway components in the blood and lungs of the Yale IPF cohort.
In aim 2 we will determine the mechanism through which NTN-1 stimulates experimentally induced lung fibrosis and in aim 3 we will define the contribution of PLXNC1 signaling pathway to the development of experimentally induced pulmonary fibrosis.
The aim of the proposed study is to elucidate the contribution of neuronally active proteins to the aberrant repair responses that characterize Idiopathic Pulmonary Fibrosis (IPF). Using several mouse models and biospecimens obtained from subjects with IPF, we propose to define the mechanisms by which these entities contribute to lung fibrosis, with the ultimate goal of developing new therapies for those suffering from this deadly disease.
Aherne, Carol M; Collins, Colm B; Rapp, Caroline R et al. (2018) Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation. JCI Insight 3: |
Bowser, Jessica L; Phan, Luan H; Eltzschig, Holger K (2018) The Hypoxia-Adenosine Link during Intestinal Inflammation. J Immunol 200:897-907 |
Lim, Grace; Facco, Francesca L; Nathan, Naveen et al. (2018) A Review of the Impact of Obstetric Anesthesia on Maternal and Neonatal Outcomes. Anesthesiology 129:192-215 |
Kiers, Dorien; Wielockx, Ben; Peters, Esther et al. (2018) Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation. EBioMedicine 33:144-156 |
Bryant, Andrew J; Shenoy, Vinayak; Fu, Chunhua et al. (2018) Myeloid-derived Suppressor Cells Are Necessary for Development of Pulmonary Hypertension. Am J Respir Cell Mol Biol 58:170-180 |
Hadi, Tarik; Boytard, Ludovic; Silvestro, Michele et al. (2018) Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nat Commun 9:5022 |
Yuan, Xiaoyi; Lee, Jae W; Bowser, Jessica L et al. (2018) Targeting Hypoxia Signaling for Perioperative Organ Injury. Anesth Analg 126:308-321 |
Yu, Guoying; Tzouvelekis, Argyris; Wang, Rong et al. (2018) Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24:39-49 |
Tzouvelekis, Argyris; Herazo-Maya, Jose D; Slade, Martin et al. (2017) Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology 22:486-493 |
Tzouvelekis, Argyrios; Yu, Guoying; Lino Cardenas, Christian L et al. (2017) SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis. Am J Respir Crit Care Med 195:500-514 |
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