Understanding the molecular link between cardiovascular disease and rheumatoid arthritis

Project: Research project

Project Details

Description

Cardiovascular disease (CVD) is a major cause of increased morbidity and mortality in rheumatoid arthritis (RA) patients, however the relationship between systemic inflammation and the development of atherosclerosis is poorly understood. Our long-term objective is to understand how the genomic programming of myeloid cells contributes to the development of CVD. RA provides an ideal model system to study how systemic inflammation increases the risk of developing cardiovascular complications. It has been suggested that RA is accompanied by myeloid skewing, a process leading to overproduction of activated myeloid cells in the bone marrow that circulate as monocytes in the blood. This may be caused by epigenomic reprogramming which is maintained in the resulting cells as they infiltrate tissues, such as the cardiovascular system, to become inflammatory macrophages. We hypothesize that the circulation of epigenomically reprogrammed monocytes as a result of myeloid skewing is linked to the development of atherosclerosis. To test this hypothesis, we use two mouse models of RA-like disease: one spontaneous (K/BxAg7) and one induced by serum transfer (STIA). Our preliminary data indicates that, unlike traditional mouse models of RA such as STIA, K/BxAg7 mice exhibit systemic inflammation and are susceptible to atherosclerosis, suggesting that they are a relevant model. In Aim 1, we profile the transcriptional and epigenomic landscape of monocytes and bone marrow progenitors in K/BxAg7, STIA, and control mice. Through computational analysis of the different models, we expect to deconvolve the distinct genomic signatures associated with atherosclerosis and arthritis. In Aim 2B, we will transplant healthy bone marrow into K/BxAg7 arthritic mice and vice versa in order to test whether myeloid skewing in the bone marrow is the source of systemic inflammation and atherosclerosis. We will measure whether these mice exhibit reduced symptoms and compare their genomic signatures. If healthy bone marrow rescues the host mouse, it will confirm the link between systemic inflammation and CVD. Given my unique training as a computational immunologist, and the support of my mentors Drs. Perlman & Thorp, we have the combined expertise to accomplish this novel, interdisciplinary research. By modeling the gene regulatory networks of myeloid cells, we can elucidate the connection between systemic inflammation & CVD.
StatusActive
Effective start/end date7/1/186/30/21

Funding

  • American Heart Association (18CDA34110224)

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