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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

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

Afonso, Milessa Silva; Verma, Narendra; van Solingen, Coen; Cyr, Yannick; Sharma, Monika; Perie, Luce; Corr, Emma M; Schlegel, Martin; Shanley, Lianne C; Peled, Daniel; Yoo, Jenny Y; Schmidt, Ann Marie; Mueller, Elisabetta; Moore, Kathryn J

Arteriosclerosis, thrombosis, & vascular biology. 2021 Mar 04; ATVBAHA120315798

Koelwyn, Graeme J; Newman, Alexandra A C; Afonso, Milessa S; van Solingen, Coen; Corr, Emma M; Brown, Emily J; Albers, Kathleen B; Yamaguchi, Naoko; Narke, Deven; Schlegel, Martin; Sharma, Monika; Shanley, Lianne C; Barrett, Tessa J; Rahman, Karishma; Mezzano, Valeria; Fisher, Edward A; Park, David S; Newman, Jonathan D; Quail, Daniela F; Nelson, Erik R; Caan, Bette J; Jones, Lee W; Moore, Kathryn J

Nature medicine. 2020 Sep; 26(9):1452-1458

Das, Saumya; Shah, Ravi; Dimmeler, Stefanie; Freedman, Jane E; Holley, Christopher; Lee, Jin-Moo; Moore, Kathryn; Musunuru, Kiran; Wang, Da-Zhi; Xiao, Junjie; Yin, Ke-Jie

Circulation. Genomic & precision medicine. 2020 Aug; 13(4):e000062

Kadosh, Bernard S; Garshick, Michael S; Gaztanaga, Juan; Moore, Kathryn J; Newman, Jonathan D; Pillinger, Michael; Ramasamy, Ravichandran; Reynolds, Harmony R; Shah, Binita; Hochman, Judith; Fishman, Glenn I; Katz, Stuart D

Arteriosclerosis, thrombosis, & vascular biology. 2020 Jul 20; ATVBAHA120314513

Sharma, Monika; Schlegel, Martin Paul; Afonso, Milessa Silva; Brown, Emily J; Rahman, Karishma; Weinstock, Ada; Sansbury, Brian; Corr, Emma M; van Solingen, Coen; Koelwyn, Graeme; Shanley, Lianne C; Beckett, Lauren; Peled, Daniel; Lafaille, Juan J; Spite, Matthew; Loke, P'ng; Fisher, Edward A; Moore, Kathryn J

Circulation research. 2020 Jul 17; 127(3):335-353

Arivazhagan, Lakshmi; Ruiz, Henry H; Wilson, Robin A; Manigrasso, Michaele B; Gugger, Paul F; Fisher, Edward A; Moore, Kathryn J; Ramasamy, Ravichandran; Schmidt, Ann Marie

Circulation research. 2020 May 22; 126(11):1565-1589

Moore, Kathryn J; Shah, Ravi

Circulation research. 2020 May 22; 126(11):1475-1476