The Role of GPR87 in Idiopathic Pulmonary Fibrosis
Abstract
Fiscal Year 2022 Peer Reviewed Medical Research Program Portfolio Category: Respiratory Health; Topic Area: Pulmonary Fibrosis; Strategic Goal: Develop and test novel treatments, including precision medicine approaches, to slow progression or reverse lung injury/disease. Pulmonary Fibrosis (PF) describes a condition in which lung tissue becomes scarred over time in response to unknown injuries, leading to shortness of breath and dry cough, that gradually progress and ultimately lead to death within 3-5 years. This condition can be idiopathic, as in idiopathic pulmonary fibrosis (IPF), or secondary to genetic disorders, lung involvement in autoimmune disorders, or to exposure to environmental toxins, chemical warfare, drugs, foreign antigens, or radiation. The most common and lethal forms, idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonia (FHP), and autoimmune pulmonary fibrosis (CTD-PF) are also more common among military personnel and Veterans. While U.S. Food and Drug Administration (FDA)-approved anti-fibrotic treatments like pirfenidone or nintedanib can slow disease progression, lung transplantation remains the only cure. Thus, novel therapeutic approaches are of supreme interest. Recently, using single cell RNA sequencing, a technology that enables to analyze the gene expression based on the RNA of each cell, we identified a specific cell population that exists only in fibrotic lungs, to which we refer as aberrant basaloid cells. These cells are located in the dense fibrotic regions of the lungs and express a rare combination of genes, including genes typically seen in basal cells, epithelial–mesenchymal transition, senescence cell markers, and most importantly, markers and regulators of fibrosis. Thus, it is thought that these cells have a major role in lung fibrosis. Indeed, since our report in 2020, these cells have been in the spotlight of multiple research projects worldwide. One of the cell membrane receptors expressed in aberrant basaloid cells, and can potentially serve as a therapeutic target, is G-protein coupled receptor 87 (GPR87). This gene is expressed exclusively in different types of cancer cells, and as we discovered recently, in fibrotic lungs, mainly in aberrant basaloid cells, and for lesser extent in basal cells, club cells, and goblet cells. We found that the expression of this gene correlates inversely with lung function and volumes. Moreover, this is a receptor of lysophosphatidic acid (LPA), a molecule that induces downstream signaling in the cell, leading eventually to fibrosis. Previously, it has been showed that blocking GPR87 led to withdrawal in cancer, in animal models. We aim to discuss the role of GPR87 in pulmonary fibrosis and the therapeutic role of GPR87 blocking or silencing, as a novel therapeutic approach for pulmonary fibrosis. First, we will isolate aberrant basaloid cells from fibrotic lungs, based on their specific markers. But because the number of these cells can be insufficient, we have succeeded previously to generate similar cells from basal cells, using aberration induction model. Second, we will co-culture these cells with different cell types: alveolar epithelial (AT) type 1 cells, AT2 and basal cells. We will discuss the effect of aberrant basaloid cells on the different cell types, based on the genetic and proteomic expression. Then we will block the expression of GPR87 and examine the effect in these cells. Second, we will use human precision cut lung slices (very thin lung slices) from healthy lung donors. Previously, using a well-documented protocol for fibrosis induction, we revealed a higher expression of GPR87. We will examine GPR87 expression blocked as a protective against fibrosis induction. Third, using bleomycin-induced lung fibrosis in a mouse model, we identified higher levels of GPR87 7 and 14 days after bleomycin injection. We will block GPR87 using different approaches, like silencing GPR87 expression, blocking
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310126
Entities
People
- Johad Khoury
Organizations
- United States Army
- Yale University