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Kathryn J. Moore

Kathryn J. Moore, PhD

Jean and David Blechman Professor of Cardiology, Department of Medicine

Professor, Department of Cell Biology

cardiovascular biology, non-coding RNA, microRNA, inflammation

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 2 diabetes. As worldwide rates of both continue to increase at an alarming pace, CVD will be the number one cause of death worldwide by 2020.

Since the introduction of the low-density lipoprotein (LDL)–lowering statins more than 20 years ago, there have been few significant breakthroughs in the treatment of atherosclerosis. To better understand the pathogenesis of atherosclerosis and identify new therapeutic targets for its treatment, my laboratory is studying two approaches thought to hold particular promise: reducing the chronic inflammation that contributes to the progression of plaques and their vulnerability to rupture, and 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 noncoding RNAs—microRNAs (miRNAs) and long noncoding RNAs—regulate inflammation and lipoprotein metabolism, and can these RNAs be manipulated for therapeutic benefit?

By investigating conventional, as well as novel, pathways in innate immunity and lipoprotein metabolism, our 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 toll-like receptor heterodimer (TLR4/TLR6) that mediates the inflammatory response to oxidized LDL and amyloid beta 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 1 beta. 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 a 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. We showed that netrin-1 is highly induced in plaque macrophages (in both humans and mice), which blocks their migration to chemokines that direct their exit from plaques. 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.

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, high-density lipoprotein (HDL) biogenesis, and fatty acid oxidation, and that targeting miR-33 in mice and nonhuman primates raised plasma HDL levels, lowered triglyceride levels, and regressed atherosclerosis. 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 immunometabolism, and that Mycobacterium tuberculosis induces the miR-33 locus to repress macrophage autophagy and fatty acid metabolism to promote intracellular bacterial survival.

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 exploring atherosclerosis and other inflammatory diseases, and they form the basis for our continuing research efforts.



Academic office

435 East 30th Street

SB 706

New York, NY 10016

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Director, Cardiovascular Research Center

PhD from McGill University

Harvard Medical School, Renal Division

Harvard Medical School, Lipid Metabolism Unit

van Solingen, Coen; Cyr, Yannick; Scacalossi, Kaitlyn R; de Vries, Maren; Barrett, Tessa J; de Jong, Annika; Gourvest, Morgane; Zhang, Tracy; Peled, Daniel; Kher, Raadhika; Cornwell, MacIntosh; Gildea, Michael A; Brown, Emily J; Fanucchi, Stephanie; Mhlanga, Musa M; Berger, Jeffrey S; Dittmann, Meike; Moore, Kathryn J

Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2022 Sep 13; 119(37):e2210321119

Ma, Liqian; Vidana Gamage, Hashni Epa; Tiwari, Srishti; Han, Chaeyeon; Henn, Madeline A; Krawczynska, Natalia; Dibaeinia, Payam; Koelwyn, Graeme J; Das Gupta, Anasuya; Bautista Rivas, Rafael Ovidio; Wright, Chris L; Xu, Fangxiu; Moore, Kathryn J; Sinha, Saurabh; Nelson, Erik R

Endocrinology. 2022 Jul 01; 163(7):

Akbar, Naveed; Braithwaite, Adam T; Corr, Emma M; Koelwyn, Graeme J; van Solingen, Coen; Cochain, Clément; Saliba, Antoine-Emmanuel; Corbin, Alastair; Pezzolla, Daniela; Møller Jørgensen, Malene; Bæk, Rikke; Edgar, Laurienne; De Villiers, Carla; Gunadasa-Rohling, Mala; Banerjee, Abhirup; Paget, Daan; Lee, Charlotte; Hogg, Eleanor; Costin, Adam; Dhaliwal, Raman; Johnson, Errin; Krausgruber, Thomas; Riepsaame, Joey; Melling, Genevieve E; Shanmuganathan, Mayooran; Bock, Christoph; Carter, David R F; Channon, Keith M; Riley, Paul R; Udalova, Irina A; Moore, Kathryn J; Anthony, Daniel; Choudhury, Robin P

Cardiovascular research. 2022 Feb 04;

Rapid neutrophil mobilization by VCAM-1+endothelial cell-derived extracellular vesicles

Akbar, Naveed; Braithwaite, Adam T.; Corr, Emma M.; Koelwyn, Graeme J.; van Solingen, Coen; Cochain, Clement; Saliba, Antoine-Emmanuel; Corbin, Alastair; Pezzolla, Daniela; Jorgensen, Malene Moller; Baek, Rikke; Edgar, Laurienne; De Villiers, Carla; Gunadasa-Rohling, Mala; Banerjee, Abhirup; Paget, Daan; Lee, Charlotte; Hogg, Eleanor; Costin, Adam; Dhaliwal, Raman; Johnson, Errin; Krausgruber, Thomas; Riepsaame, Joey; Melling, Genevieve E.; Shanmuganathan, Mayooran; Bock, Christoph; Carter, David R. F.; Channon, Keith M.; Riley, Paul R.; Udalova, Irina A.; Moore, Kathryn J.; Anthony, Daniel; Choudhury, Robin P.

Cardiovascular research. 2022;

Koelwyn, Graeme J; Aboumsallem, Joseph Pierre; Moore, Kathryn J; de Boer, Rudolf A

Journal of molecular & cellular cardiology. 2021 Sep 25; 163:1-8

Barrett, Tessa J; Corr, Emma M; van Solingen, Coen; Schlamp, Florencia; Brown, Emily J; Koelwyn, Graeme J; Lee, Angela H; Shanley, Lianne C; Spruill, Tanya M; Bozal, Fazli; de Jong, Annika; Newman, Alexandra A C; Drenkova, Kamelia; Silvestro, Michele; Ramkhelawon, Bhama; Reynolds, Harmony R; Hochman, Judith S; Nahrendorf, Matthias; Swirski, Filip K; Fisher, Edward A; Berger, Jeffrey S; Moore, Kathryn J

Cell reports. 2021 Sep 07; 36(10):109595

Schlegel, Martin Paul; Sharma, Monika; Brown, Emily J; Newman, Alexandra Ac; Cyr, Yannick; Afonso, Milessa Silva; Corr, Emma M; Koelwyn, Graeme J; van Solingen, Coen; Guzman, Jonathan; Farhat, Rubab; Nikain, Cyrus A; Shanley, Lianne C; Peled, Daniel; Schmidt, Ann Marie; Fisher, Edward A; Moore, Kathryn J

Circulation research. 2021 Aug 20; 129(5):530-546

Afonso, Milessa Silva; Sharma, Monika; Schlegel, Martin Paul; van Solingen, Coen; Koelwyn, Graeme J; Shanley, Lianne C; Beckett, Lauren; Peled, Daniel; Rahman, Karishma; Giannarelli, Chiara; Li, Huilin; Brown, Emily J; Khodadadi-Jamayran, Alireza; Fisher, Edward A; Moore, Kathryn J

Circulation research. 2021 Apr 16; 128(8):1122-1138