Inflammation and Metabolic Reprogramming of Lupus Monocytes - Mechanisms of the Pathobiology of Lupus Cardiovascular Disease
Abstract
What types of patients will it help and how will it help them? Lupus is a systemic disease where organs are attacked due to dysfunction of the immune system. Lupus occurs in approximately 0.1% to 0.3% in the United States, affecting women in their childbearing years with devastating consequences for both patients and their families. Women, non-Hispanic black, and Hispanic active duty military personnel have elevated lupus rates, with resultant time away from active duty/work and adverse health consequences. Despite improvement in lupus treatment over the last half century, cardiovascular disease is the leading killer of these young women with lupus. As a systemic disease, young women with lupus often experience chest pain (angina) and an increased risk of cardiac events such as heart attacks and strokes. While many young women have lupus, the effects of the disease can vary widely, making treatment decisions a significant challenge to patients and physicians. This research will examine why some women with lupus get heart disease and why others do not, leading to a better understanding of how to prevent and treat lupus-related organ damage. What are the potential clinical applications, benefits, and risks? While overactivation of the immune system and inflammation are known to drive the development of lupus, how the immune system and inflammation contribute to heart disease in lupus is currently unknown. Recently, the pathways that regulate how immune cells regulate energy usage and production (a process termed immunometabolism) have been linked to the development of many inflammatory diseases, including heart disease. We will study a type of heart disease called coronary microvascular dysfunction, often found in women with lupus, to understand if alterations in immunometabolism play a role in the presence and severity of their heart disease. This research may lead to new preventive, detection, and treatment strategies for Service members, Veterans, and beneficiaries that are affected by lupus. The research uses medically approved, safe, noninvasive methods, similar to blood and urine sample testing, to take pictures of the heart. What is the projected time it may take to achieve a patient-related outcome? The current application will take 3 years to acquire state-of-the-art cardiac imaging techniques and immune function tests in 40 women with lupus. We will determine if a biomarker panel exists that will identify whether a woman with lupus does or does not have heart disease. This will serve as a platform for next-step clinical trials, which would take an additional 3 to 5 years. For example, we hope to uncover new mechanistic pathways that drive heart disease in lupus that would lead to testing already-approved medications for lipid lowering, regulating blood sugar, cellular metabolism, and inflammation as treatment of heart disease in lupus. What is the likely impact of this study on the understanding, prevention, diagnosis, and/or treatment of lupus? The cardiovascular system supplies all tissues and organs of the body and thus represents a window of opportunity for improved understanding of lupus variability and why some women get heart disease and others do not. Further work, beyond the current application, will include using the identified biomarker panels for identifying specific lupus subtypes of heart disease. We will also test specific treatments aimed at the biomarkers such as medications currently used for heart disease (metformin, statins) and new agents (monoclonal antibody therapies such as canakinumab) shown to be effective for heart disease in clinical trials. Our currently proposed projects, combined with future work, will provide the necessary building blocks of understanding needed for new preventive, diagnostic, and treatment strategy development to improve outcomes for Service members, Veterans, and beneficiaries that are affected by lupus.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810709
Entities
People
- Caroline Jefferies
Organizations
- Cedars-Sinai Medical Center
- United States Army