Biosketch / Results /
Kathryn MooreJean and David Blechman Professor of Cardiology, Department of Medicine
Professor, Department of Cell Biology
522 First Avenue
New York, NY 10016
Major Research Interests
Atherosclerosis is the number one cause of death in the United States. Cardiovascular disease (CVD) risk is greatly increased by metabolic diseases such as dyslipidemias and type II diabetes, which continue to increase at an alarming rate world-wide, so much so that CVD will be the number one cause of death world-wide by 2020. Since the introduction of the statin class of LDL-lowering drugs over 20 years ago, there have been few significant breakthroughs in the treatment of atherosclerosis. Therefore, there is an unremitting need to better understand the pathogenesis of atherosclerosis and to identify new therapeutic targets for its treatment. Two approaches are thought to hold particular promise: (1) Reducing the chronic inflammation that contributes to the progression of plaques and their vulnerability to rupture; and, (2) Promoting cholesterol efflux from lipid-laden macrophages in plaques and increasing reverse cholesterol transport to promote cholesterol removal from the body. My laboratory uses both hypothesis-driven and unbiased approaches to address two outstanding questions:
- What underlies the chronic activation of the innate immune system in atherosclerosis and why does resolution of inflammation fail to occur?
- How do non-coding RNAs (microRNAs, lncRNAs) regulate lipoprotein metabolism and inflammation, and can these RNAs be manipulated for therapeutic benefit?
By investigating conventional, as well as novel, pathways in innate immunity and lipoprotein metabolism, my research has significantly advanced our knowledge in both of these areas:
First, we discovered new pathways that mediate the innate immune response to altered-self ligands that accumulate in atherosclerosis and Alzheimer’s disease: a new TLR heterodimer (TLR4/TLR6) that mediates the inflammatory response to oxidized-LDL and b-amyloid (Stewart et al. 2010. Nature Immunology), and a CD36-mediated pathway that mediates the intracellular conversion of these soluble ligands into crystals or fibrils that activate the NLRP3-inflammasome and secretion of interleukin-1b (Sheedy et al. 2013. Nature Immunology). These studies identified long-sought mechanisms for how endogenous ligands that accumulate in atherosclerosis and Alzheimer’s disease trigger chronic innate immune activation.
Second, in the quest to understand why macrophages persist in tissues in atherosclerosis and obesity-induced insulin resistance, we uncovered new roles for neuronal guidance molecule in the pathophysiology of chronic inflammation. We found that netrin-1, originally described as a neuronal guidance cue, acts as a negative regulator of leukocyte migration via its receptor Unc5b (Ly et al. PNAS. 2005). We showed that netrin-1 is highly induced in human and mouse plaque macrophages, which blocks their migration to chemokines directing macrophage exit from plaques (van Gils et al. Nature Immunology, 2012). Furthermore, we showed that netrin-1 is also induced in the setting of diet-induced obesity and acts to promote macrophage retention in adipose tissue leading to insulin resistance (Ramkhelawon et al. Nature Medicine, 2014).
Third, we identified miR-33a and miR-33b as intronic miRNAs of the SREBF2 and SREBF1 genes, and showed that they cooperate with their host gene products to balance cellular lipid levels. We showed that miR-33 represses cholesterol efflux, HDL biogenesis and fatty acid oxidation, and that targeting of miR-33 in mice and non-human primates raised plasma HDL, lowered triglycerides, and regressed atherosclerosis (Rayner et al. 2010. Science; Rayner et al. 2011. J. Clin. Invest; Rayner et al. 2011. Nature). These findings broke open the field of miRNA regulation of lipoprotein metabolism, and showed the potential of miRNAs as therapeutic targets in atherosclerosis. Since those initial discoveries, we have also shown that miR-33 regulates macrophage inflammatory polarization by altering cellular immumetabolism (Ouimet et al. J. Clin. Invest; 2015); and that Mycobacterium tuberculosis induces the miR-33 locus to repress macrophage autophagy and fatty acid metabolism to promote intracellular bacterial survival (Ouimet et al. 2016).
Taken together, these innovative studies have had important impacts, ranging from new insights into innate immunity and lipid metabolism to the identification of novel therapeutic targets for CVD. Each of these seminal discoveries has opened up new avenues for exploration of atherosclerosis and other inflammatory diseases, and they form the basis for our continuing research efforts.
Research Keywordscardiovascular biology, non-coding RNA, microRNA, inflammation
Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism
Maus, Mate; Cuk, Mario; Patel, Bindi; Lian, Jayson; Ouimet, Mireille; Kaufmann, Ulrike; Yang, Jun; Horvath, Rita; Hornig-Do, Hue-Tran; Chrzanowska-Lightowlers, Zofia M; Moore, Kathryn J; Cuervo, Ana Maria; Feske, Stefan. Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell metabolism. 2017 Jan 26;25(3):698-712 (2424992)
In vivo immune cell screening of a nanoparticle library improves atherosclerosis therapy
Tang, J; Baxter, S; Menon, A; Sanchez-Gaytan, B; Fay, F; Zhao, Y; Ouimet, M; Braza, M S; Alaarg, A; Longo, V A; Abdel-Atti, D; Duivenvoorden, R; Storm, G; Tsimikas, S; Moore, K J; Swirski, F; Nahrendorf, M; Fisher, E A; Perez, Medina C; Fayad, Z A; Reiner, T; Mulder, W J. In vivo immune cell screening of a nanoparticle library improves atherosclerosis therapy [Meeting Abstract]. Molecular imaging & biology. 2016 December;Conference:(World):S10-S12 (2415692)
Immune cell screening of a nanoparticle library improves atherosclerosis therapy
Tang, Jun; Baxter, Samantha; Menon, Arjun; Alaarg, Amr; Sanchez-Gaytan, Brenda L; Fay, Francois; Zhao, Yiming; Ouimet, Mireille; Braza, Mounia S; Longo, Valerie A; Abdel-Atti, Dalya; Duivenvoorden, Raphael; Calcagno, Claudia; Storm, Gert; Tsimikas, Sotirios; Moore, Kathryn J; Swirski, Filip K; Nahrendorf, Matthias; Fisher, Edward A; Perez-Medina, Carlos; Fayad, Zahi A; Reiner, Thomas; Mulder, Willem J M. Immune cell screening of a nanoparticle library improves atherosclerosis therapy. Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2016 Nov 01;113(44):E6731-E6740 (2288872)
Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis
Mediero, Aranzazu; Wilder, Tuere; Ramkhelawon, Bhama; Moore, Kathryn J; Cronstein, Bruce N. Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB journal. 2016 Nov;30(11):3835-3844 (2213582)
Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice
Giles, Daniel A; Ramkhelawon, Bhama; Donelan, Elizabeth M; Stankiewicz, Traci E; Hutchison, Susan B; Mukherjee, Rajib; Cappelletti, Monica; Karns, Rebekah; Karp, Christopher L; Moore, Kathryn J; Divanovic, Senad. Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice. Molecular metabolism. 2016 Nov;5:1121-1130 (2303622)