Systemic Sclerosis (SSc) is a multisystem disorder affecting the whole body and leading to fibrosis of the skin, heart, kidneys, and lungs. Although the skin symptoms are the most visible and likely to lead to diagnosis, it is the cardiac and pulmonary symptoms that are the leading cause of death in SSc patients. Many of the medications currently in use are aimed at particular organs and their underlying mechanism of action is often unknown. Based on the systemic nature of the disease, it seems likely that circulating cells play a role in propagating the pro-fibrotic signals to distinct tissues. Our previous work using a mouse model has shown that monocytes from the blood infiltrate the lung causing inflammation that leads to pulmonary fibrosis. Further, in our preliminary data, we demonstrate that monocytes from SSc patients exhibit distinct transcriptional profiles form healthy controls. Thus, we propose that circulating monocytes will exhibit a molecular signature of fibrosis that precedes their infiltration into the tissues where they differentiated into pro-fibrotic macrophages. To test this hypothesis, we will use a novel mouse model of systemic fibrosis that is based on an implanted Alzet mini-pump releasing bleomycin over time. In Aim1, we will assay the transcriptome (RNA-seq) and epigenome (ATAC-seq and ChIP-seq) of blood monocytes vs. monocyte-derived lung macrophages in mice with induced SSc-like fibrosis. Through bioinformatic analysis, we will compare the expression profiles and chromatin landscapes with control mice along the process of differentiation. Using our computational pipeline that integrates the data from multi-omics assays, we will identify key regulatory factors representing the fibrotic signature in the transition from circulating to lung-infiltrating monocytes. We expect to identify specific factors shared between blood monocytes and lung macrophages that represent the signature of fibrosis. In Aim2, we will compare this fibrotic signature from mice to that of human disease. We will analyze the transcriptional profiles from circulating monocytes of early SSc patients and matched controls in order to identify the impact of the disease on their transcriptional programming. This approach will take into consideration the variability across SSc patients in identifying regulatory modules associated with disease. We intend to establish the relevance of the mouse model and the conservation of the fibrotic signature across species. Together, these results will serve as pilot data to further study the process of fibrosis across tissues and assess the effect of different interventions in the implanted bleomycin mouse model. Moreover, we propose to leverage this initial study in human patients to incorporate a larger cohort and link specific phenotypes and individual variation to the genomic profile. As a computational biologist with extensive experience in the execution, design, and analysis of immunogenomic studies, I am uniquely qualified to head this study. Our long-term goal is to understand the underlying mechanism of SSc and explain its body-wide effect. This proposal represents a novel, interdisciplinary approach to understanding SSc and will be an important step towards identifying therapeutic targets for future treatments.
|Effective start/end date||4/1/18 → 3/31/20|
- Scleroderma Foundation (Agmt 03/29/18)