Innate Immunity plays a fundamental role in atherogenesis and our work has provided an improved understanding of this by demonstrating that "oxidation-specific epitopes" (OSE), which are generated on oxidatively damaged molecular complexes, such as OxLDL and apoptotic cells, are major targets of innate pattern recognition receptors, such as lgM Natural Antibodies (NAbs). During the first cycle, we demonstrated that 20-30% of all lgM NAbs bind to OSE in both mice and humans, and we proposed that lgM OSE-NAbs have been conserved to provide homeostasis to the many OSE generated in both health and disease. Considerable data support an atheroprotective role for lgM in murine models and lgM titers in humans are inversely related to cardiovascular disease (CVD). In the renewal, we will focus on understanding the role of NAbs in mice and humans, and define the mechanisms that regulate 8-1 cells that generate NAbs.
Specific Aim 1 will define the repertoire and prevalence of OSE NAbs in mice and humans. We will generate a B-1 cell derived database of lgM NAb heavy chain variable (IGHV) CDR3 sequences and their relative expression in both humans and mice. We will then sort OSE-B-1 cells to annotate OSE NAbs, and will examine their relative expression under experimental models of inflammation and atherosclerosis in mice, and in epidemiological studies in humans.
Specific Aim 2 will define the roles of OSE NAbs and B-1 cells in inflammation and atherogenesis. Using transgenic mice expressing OSE antibodies, we will seek to define the mechanisms by which OSE-Abs influence inflammation and atherosclerosis. Because these NAbs target prevalent oxidized lipids in atherosclerotic lesions, these studies should define the importance of these oxidized moieties in mediating inflammation and atherogenesis.
Specific aim 3 will test the hypothesis that vital functions of B-1 cells, such as proliferation and secretion of NAbs are positively regulated by TLRs, while the nuclear receptors GRand LXR negatively regulate B-1 cells. We will determine the impact of these immune modulators on transcriptional regulation of B-1 cells in comparison to B-2 cells and macrophages, to provide an improved understanding of the integrated responses to these immune cell regulators. These studies should yield new insights into the important role that innate immunity plays in inflammation and atherosclerosis, and may lead to novel diagnostic and therapeutic approaches for CVD.

Public Health Relevance

The proposed studies will be of significance in improving our understanding of how immune mechanisms provide protection against oxidative stress that occurs in both health and disease. This information may lead to novel diagnostic and therapeutic applications for humans with inflammatory diseases and atherosclerosis.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
van der Valk, Fleur M; Bekkering, Siroon; Kroon, Jeffrey et al. (2016) Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation 134:611-24
Zhao, Xuan; Hirota, Tsuyoshi; Han, Xuemei et al. (2016) Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation. Cell 165:1644-57
Wang, Junjian; Zou, June X; Xue, Xiaoqian et al. (2016) ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med 22:488-96
Verbeek, Rutger; Boekholdt, S Matthijs; Stoekenbroek, Robert M et al. (2016) Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study. J Lipid Res 57:697-705
Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok et al. (2016) Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res 57:706-13
Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping et al. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 126:2855-66
Wall, Christopher E; Yu, Ruth T; Atkins, Anne R et al. (2016) Nuclear receptors and AMPK: can exercise mimetics cure diabetes? J Mol Endocrinol 57:R49-58
Liu, Weilin; Struik, Dicky; Nies, Vera J M et al. (2016) Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 113:2288-93
Ley, Klaus (2016) 2015 Russell Ross Memorial Lecture in Vascular Biology: Protective Autoimmunity in Atherosclerosis. Arterioscler Thromb Vasc Biol 36:429-38
Miller, Yury I; Shyy, John Y-J (2016) Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation. Trends Endocrinol Metab :

Showing the most recent 10 out of 113 publications