Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Studies over the last decade suggest that failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Accordingly, two critical unanswered questions are: (a) what are the endogenous mechanisms underlying dysregulated resolution programs in atherosclerosis and (b) what mechanism-based treatment strategies can be conceived to initiate resolution when it fails. The resolution of inflammation is regulated by specialized pro-resolving mediators (SPMs) that comprise omega-6 derived lipoxins and omega-3 derived resolvins, protectins and maresins. The overall objective of this proposal is to understand the mechanisms of dysregulated resolution in atherosclerosis and to harness SPM signaling pathways towards a novel treatment strategy. A critical enzyme in the biosynthesis of lipoxins and resolvins, 5- lipoxygenase (5-LOX) is expressed in M?s, which are abundant in atherosclerosis. This proposal is to test the hypothesis that SPM, via 5-LOX in M?s, limit progression and enhance lesion regression in atherosclerosis.
Aim 1 will explore the hypothesis 5-LOX is protective in atherosclerosis. Using chimeric Ldlr-/--5-LOX-/- mice, Sub aim I-A and B will investigate new in vivo mechanisms that underscore how 5-LOX is protective against atherosclerosis progression and regression respectively.
Aim 2 will test the hypothesis, and investigate the mechanisms therein, that the 5-LOX-derived SPM resolvin D1 (RvD1) promotes inflammation resolution and plaque stabilization in atherosclerosis. Using Ldlr-/- mice fed on a synthetic diet to induce atherosclerosis, I will investigate whether RvD1 is protective in two clinically relevant models of atherosclerosis;one that simulates aggressive lipid lowering (Sub aim II-A) and one where hyperlipidemia is intact (Sub aim II-B).
Aim 3 will explore the hypothesis the RvD1 regulates 5-LOX by controlling the balance between pro-inflammatory (e.g. leukotriene B4) and pro-resolving mediators (e.g. lipoxin A4), a key mechanism of resolution. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with the skills needed to become an independent scientist in cardiovascular research. During the K99/Mentored phase of the award the applicant will continue to gain expertise molecular, cellular and biochemical approaches to study the dysregulated resolution in atherosclerosis from a mechanistic standpoint. An advisory committee of established scientists/mentors in the fields of resolution, CVD and translational science will guide the candidate in her transition to scientific independence over the course of the award period.

Public Health Relevance

Cardiovascular diseases such as atherosclerotic vascular disease, is the leading cause of death in the industrialized world. Current studies suggest that failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. This project will provide a new understanding of the mechanisms that contribute to failed resolution and will provide new avenues for the treatment of atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-P (M2))
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Carlson, Drew E
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Fredman, Gabrielle; Tabas, Ira (2017) Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol 187:1211-1221
Doran, Amanda C; Ozcan, Lale; Cai, Bishuang et al. (2017) CAMKII? suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest 127:4075-4089
Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568
Fredman, Gabrielle; Spite, Matthew (2017) Specialized pro-resolving mediators in cardiovascular diseases. Mol Aspects Med 58:65-71
Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859
Kamaly, Nazila; Fredman, Gabrielle; Fojas, Jhalique Jane R et al. (2016) Targeted Interleukin-10 Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis. ACS Nano 10:5280-92
Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2016) MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A 113:6526-31
Westrick, Randal; Fredman, Gabrielle; Early Career Committee (2015) Platelets: Context-Dependent Vascular Protectors or Mediators of Disease. Arterioscler Thromb Vasc Biol 35:e25-9
Fredman, Gabrielle; Kamaly, Nazila; Spolitu, Stefano et al. (2015) Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med 7:275ra20
Libby, Peter; Tabas, Ira; Fredman, Gabrielle et al. (2014) Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867-79

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