Post-Transcriptional Regulation of Collagen in Systemic Sclerosis
Abstract
Scientific Objective: Systemic sclerosis (SSc) is a disease where our immune system—which normally protects us from infection—turns inward and injures our organs. In particular, SSc—also known as scleroderma—causes fibrosis or scarring in our organs. When our organs are scarred, they do not function normally. The interest in our laboratory is to understand scarring in the lung or pulmonary fibrosis caused by SSc. Scarring develops when cells called fibroblasts synthesize proteins known as collagens. When fibroblasts appear in the lung in SSc, they deposit collagen in the parts of the lung that we use to breathe. Pulmonary fibrosis can lead to breathlessness, respiratory failure, and death. Our laboratory has been interested in understanding how fibroblasts in SSc make collagen and how we can stop these cells from making collagen in pulmonary fibrosis. Collagen proteins are made from molecules called messenger ribonucleic acid or mRNA. Cells need collagen mRNA to make collagen proteins. Cells make and break down collagen mRNA all the time. We hypothesize that collagen mRNA in SSc is stabilized. This means that collagen mRNA is not being broken down like it normally should. This leads to more collagen mRNA and therefore more collagen protein. Our objective is to understand how fibroblasts in SSc stabilize collagen mRNA so that we can eventually develop drugs to disrupt collagen mRNA stabilization and stop fibrosis in the lung. Idea Development Award Focus Area: The goal of this application is to obtain a bird’s eye view of collagen mRNA stabilization in SSc. This process is not well understood. We suggest that the successful completion of our study will identify new targets for drug development in SSc. In this study: (1) We will purify collagen mRNA from fibroblasts derived from the lungs of patients with SSc. We will use a special procedure called mass spectrometry to identify all the proteins—called RNA-binding proteins— that are attached to collagen mRNA. (2) There are many different kinds of fibroblasts in the lung. We will identify which fibroblasts in the lung express these RNA-binding proteins. (3) Finally, we will grow fibroblasts in the laboratory and determine how these cells make collagen when we block these RNA-binding proteins. By understanding this basic process of collagen mRNA stabilization in SSc, we hope to apply what we learn in this study to develop new drugs to help patients with SSc who suffer from pulmonary fibrosis. If we can disrupt collagen mRNA stabilization in SSc, we think we can stop cells from making collagen to help stop and potentially reverse pulmonary fibrosis. Before we can disrupt collagen mRNA stabilization, we need to know how fibroblasts stabilize collagen mRNA. When we know what proteins are attached to collagen mRNA, we can block these proteins with certain drugs with the goal of de-stabilizing collagen mRNA. Furthermore, if we are successful, we will disrupt collagen mRNA stabilization in SSc, which will help SSc patients live longer and breathe more easily. We expect that our study will take 2 years. When we can publish our findings, we hope to interest other collaborators to develop drugs to target collagen mRNA stabilization to accelerate drug development. Our study is innovative because, to our knowledge, our techniques in the laboratory to purify collagen mRNA have never been applied to SSc or to any other fibrotic disease. If we are successful, we suggest that our approach will serve as a model for studying other fibrotic diseases. Our research team includes physicians with expertise in pulmonary fibrosis and SSc (Kass, Lafyatis) and biologists with expertise in mRNA (Berman). In summary, we have proposed a study to understand how fibroblasts cause scarring by understanding collagen mRNA stabilization at the molecular level. Our goal is to understand this process and ultimately to develop new therapies to improve the lives of patients who suffer from
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210422
Entities
People
- Daniel Kass
Organizations
- United States Army
- University of Pittsburgh