Regulation of Profibrotic SPP1-Expressing Macrophages by TFEB in SSc-ILD
Abstract
Scleroderma is associated with complications involving several different organs, but the most lethal complications involve the lungs. Scleroderma-associated interstitial lung disease is the most common complication leading to death of patients with scleroderma. However, the cause of scleroderma-interstitial lung disease is not well understood. The current understanding is that as part of the autoimmune process inflammatory cells infiltrate the lungs. These inflammatory cells in turn stimulate cells in the lung known as fibroblasts to turn into scarring cells known as myofibroblasts. These scarring cells disrupt lung function preventing normal gas exchange in lungs. The goal of our application is to understand the inflammatory cells, known as macrophages, that appear most important in provoking this transition of fibroblasts into scarring myofibroblasts. Thus, we are addressing the following Focus Area: Define functional role of epigenetic changes, multiple cell types, and molecules that mediate pathogenesis and/or initiate or propagate organ-specific disease activity using preclinical models and clinical samples. We propose to examine the epigenetic state of the macrophages in patients with scleroderma lung disease. We will take advantage of the lung transplantation program at the University of Pittsburgh, permitting us to examine macrophages directly from patients undergoing lung transplantation. The lung transplantation program at the University of Pittsburgh is distinctive nationally and internationally for the large number of scleroderma patient receiving lung transplants. This provides us with unprecedented opportunities to understand this lethal complication, studying the lungs that are removed from these patients when they are given healthy donor lungs. We will use an advanced technology that permits us to look at the structure of the DNA on a cell-by-cell basis to examine the molecular changes in the cells from these lungs. This technology allows us to see how the structure of the DNA and how this structure is altered in macrophages from the lungs of patients with scleroderma- associated interstitial lung disease. By understanding how the DNA structure is altered we can understand the molecules, known as transcription factors, regulating this process. Our preliminary data implicate one molecule, Transcription factor EB, as particularly important. So, our studies will focus on this molecule and the mediators released by other cells in the lungs that stimulate it. These studies are designed to help lung disease in these scleroderma patients with interstitial lung disease by discovering molecular pathways that might be blocked by new drugs. Two types of drugs might be developed based on our proposed studies. The first type would be drugs designed to block levels of Transcription factor EB. We will test the effect of a currently available drug that increases the level of Transcription factor EB. Our studies would clarify the need to develop drugs that inhibit this molecule and associated pathways. In addition, we will also test the role of factors released by neighboring cells known as cytokines on Transcription factor EB. Inhibiting cytokines that stimulate Transcription factor EB would be a second approach to blocking disease-associated macrophages and thus the disease process. Our proposed studies pose no risk to patients since the lung samples that will be used for this research are otherwise discarded when patients receive healthy lung transplants. Although the proposed studies will take time to translate into therapeutic advances, such research is key to a detailed understanding of the disease process that will ultimately unravel the pathways that control the scarring in lungs of these patients. Current therapies available for the disease, including nintedanib and tocilizumab, have modest effects on scleroderma-associated interstitial lung disease progression. More effective treatments, such as immunoablatio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210512
Entities
People
- Harinder Singh
Organizations
- United States Army
- University of Pittsburgh