Understanding Glucose Metabolism in the Development and Treatment of Lupus
Abstract
Rationale, Objective, Aims: Lupus is an autoimmune disease characterized by immune-system cells that are autoreactive, i.e., they attack the body’s own tissues rather than foreign pathogens. Currently, lupus lacks a cure, and treatment focuses on alleviating symptoms or on immunosuppression, i.e., suppression of the overall immune system, including normally functioning immune cells. There is a distinct lack of understanding of lupus initiation and the biological changes that take place to support progression of this disease. Emerging evidence points to abnormal glucose metabolism – the use of glucose as an energy source – in the development of lupus and other autoimmune diseases in both humans and mice. Inhibition of glucose metabolism is therefore an attractive approach for attenuating the highly energetic cells that drive lupus disease while potentially avoiding immunosuppression. We have tested the potential of inhibiting glucose metabolism in multiple mouse models that naturally develop a lethal autoimmune disease resembling human lupus. Specifically, we treated the mice with 2-deoxy-D-glucose (2DG), a compound that limits glucose metabolism, and showed that 2DG treatment is highly effective in reversing lupus-like symptoms and extending lifespan in these mice. However, little is known about how 2DG reverses this disease, hindering testing of 2DG in humans. For example, before 2DG can be tested in humans, it is necessary to identify the specific metabolic pathways impacted by 2DG in mice and humans, to ensure that application of this promising therapy in humans inhibits the same types of autoreactive cells in lupus patients that is does in mice with lupus. To address these knowledge gaps, we will, in Aim 1, identify metabolic-pathway changes that develop as disease progresses in mouse models of lupus and in blood from lupus patients, and compare the mouse and human data to find common alterations that can be targeted. In Aim 2 we will analyze the effects of 2DG on different metabolic pathways in treated mice; test the effects of 2DG treatment on patient cells; and compare these mouse and human data. Our work will identify metabolic pathways altered in lupus development and those impacted by 2DG, laying the groundwork for understanding how abnormal metabolism affects lupus development; identifying the key types of immune cells involved; and ascertaining metabolic-pathway components that represent potential targets for development of improved therapies. Focus Areas: This project addresses two Fiscal Year 2022 Lupus Research Program Focus Areas: (1) Understanding the biological mechanisms of lupus disease…; (2) Improving quality of life for individuals living with lupus including…symptom and disease control, and comparative effectiveness research. Applicability of the Research: Completion of this project will greatly expand our knowledge of metabolic dysfunctions that occur in lupus progression as well as those that, when normalized via 2DG treatment, offer therapeutic benefits. These data will not only stimulate development of novel metabolism-based therapies for treating lupus, but will also identify potential therapeutic targets related to specific clinically defined characteristics of human lupus patients. The additional information that we will reveal on metabolic aberrations that either lead to or are caused by lupus disease progression may aid in the diagnosis of lupus. These data, paired with information on how 2DG affects metabolic pathways, have potential to greatly improve the health and quality of life of all lupus patients. Should this treatment become available to lupus patients, it has the potential to reverse the disease by specifically targeting autoimmune cells, leaving the normal immune cells unaffected and effectively limiting the immunosuppression that is a side effect of many current lupus therapies. Moreover, in our mouse models, 2DG has been shown to elicit increased therapeu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310308
Entities
People
- Lucas Chang
Organizations
- Jackson Laboratory
- United States Army