The Marc and Ruti Bell Program in Vascular Biology and Disease

At the Marc and Ruti Bell Vascular Biology and Disease Research Program we investigate the mechanisms involved in the development and progression of cardiovascular disease and related conditions at the cellular and molecular levels.  Given the significant health burden of heart disease, with it being the leading cause of morbidity and mortality worldwide, we are particularly concerned with studying those factors that will lead to innovations in diagnosis, treatment, and prevention. Our close connection to the Center for the Prevention of Cardiovascular Disease and its physicians in clinical practice and clinical research at NYU Langone Medical Center encourages a truly translational approach, allowing for our research findings to be applied to the development of new patient care strategies to improve preventive cardiology treatments and outcomes.

 

History & Leadership

The Vascular Biology and Disease Program was established by a generous gift from Marc and Ruti Bell in 2003.  Edward A. Fisher, MD, PhD, came to NYU at this time with a mandate to establish a preventive cardiology center and foster research, clinical, and educational advances in this area.  With an extensive research background in lipid/lipoprotein metabolism and atherosclerosis, he was appointed both Director of the Vascular Biology and Disease Program as well as the Director of The Center for the Prevention of Cardiovascular Disease.  As the Leon H. Charney Professor of Cardiovascular Medicine, Dr. Fisher continues to lead these programs today.  In 2010 he recruited Kathryn Moore, PhD, from Harvard to join NYU and the Bell Program, where she is now Professor of Medicine and Cell Biology.  For over a decade Dr. Moore has worked to shed light on the pathways of chronic inflammation and dysregulation in cardiovascular disease, type II diabetes, and Alzheimer’s.  Around this time the Bell Program welcomed the addition of Jeffrey Berger, MD, Assistant Professor in the Departments of Medicine and Surgery, an accomplished preventive cardiologist whose work in platelets and their roles in heart attacks further expands the research spectrum. His work on platelet activity in high-risk patients and the response of platelets to antiplatelet and antithrombotic therapeutics has contributed significant information on the role these clotting factors. 

 

Our Work

Working within a state-of-the-art facility in the Smilow Research Center, our group of distinguished researchers conducts basic science investigations into the factors important in the pathogenesis of CVD and associated conditions. Bell Program research activities are funded by a combination of foundation and federal awards, in addition to philanthropy.

A highlight of our work includes the following achievements and projects:

(1) The cell biology of hepatic lipid and lipoprotein metabolism: Dr. Fisher’s lab was the first to demonstrate the degradation of apoprotein B (apoB) as regulated by dietary fatty acids, a process that may also be regulated by insulin. Importantly, this non-proteasomal pathway may be dysregulated in insulin-resistance associated with type II diabetes or obesity, and thereby contribute to the over-production of atherogenic lipoproteins that increase the risk of coronary artery disease in these metabolic states. To further pursue the proteasomal and non-proteasomal regulation of apoB degradation, Bell Program researchers are using cell and molecular biological approaches on experimental models as diverse as cell-free systems and tissue-specific knockout mice.

(2) Investigation of the molecular biology of vascular diseases and non-invasive imaging techniques: The Fisher Lab investigates the molecular factors that regulate the progression and regression of atherosclerotic plaques. Our research relies on mouse models of atherosclerosis and current projects focus on the regression of plaques after the normalization of hyperlipidemia, and the effects of HDL on plaque progression and regression.  To get at the molecular levels that regulate changes induced by the various experimental conditions in specific arterial wall cell types, our group has pioneered the use of laser capture microdissection to isolate plaque macrophages in order to study gene expression. Recently, by using novel mouse models and these powerful techniques, we have observed and reported that foam cells can leave plaques during regression and they require dendritic cell properties for this emigration. With collaborators at Mt. Sinai School of Medicine we have recently shown that HDL particles can be converted to nanoplatforms to deliver MRI enhancing agents to plaques to better visualize them. Our goal is to adapt these particles for molecular imaging purposes.

(3) miR33 Regulation of Cholesterol Efflux and HDL Formation: Dr. Moore and colleagues have revealed the role of microRNA 33 (miR33) as a regulator of cholesterol efflux from cells and the formation of HDL, and in a follow up project, Dr. Moore’s lab demonstrated that these findings have highligan antagamir of miR33 can regress atherosclerotic lesions, and that miR33 antagamirs raises HDL levels and lowered VLDL levels in animal models. These findings reveal the important role that miRNAs play in lipoprotein metabolism and open new avenues for the treatment of dyslipidemias.

(4) Platelet and Hypercoagulable Mechanisms of Cardiovascular Disease: Within the Bell Program laboratory Dr. Berger’s team studies platelet activity using various techniques, including whole blood and platelet rich plasma aggregometry, flow cytometry, hematology analysis, and molecular biology using the platelet transcriptome. The goal of the group is to use the platelet phenotype in understanding who is at risk for developing cardiovascular disease and to determine whether modification of the platelet phenotype can ultimately lower the risk of adverse cardiovascular events.

(5) Immune Reaction and Inflammation’s Impact on Vascular Pathology: Dr. Moore and Dr. Fisher have been pursuing how specific molecules are drivers of the chronic immune reaction in cardiovascular disease. They have been able to show that a protein called netrin-1 can promote inflammation and atherosclerosis. Through new projects, Bell Program researchers are seeking to understand attributes of adipose tissue that may contribute to localized and systemic inflammation and insulin resistance in obesity by exploring the role of netrin-1 further.

With each step forward the Bell Program expands its integrative approach to collaborate with researchers conducting related work.  We have recently begun working closely with researchers in the Division of Endocrinology at NYULMC including Ann Marie Schmidt, MD, Professor of Medicine, Pharmacology and Pathology and Ira Goldberg, MD, Clarissa and Edgar Bronfman, Jr. Professor of Endocrinology. With these distinguished colleagues we further investigate how macrophages impact diabetic-induced inflammation in atherosclerosis and obesity. We will also be working together on pre-clinical investigations of therapies to improve cardio-metabolic complications of obesity in the coming years.

 

Recent Bell Program Awards & Honors

  • Dr. Edward Fisher, Dr. Kathryn Moore, and Dr. Ann Marie Schmidt received a P01 award from the National Heart, Lung, and Blood Institute (NHLBI) for $12 million over 5 years to fund their collaborative research project, “Macrophage Dysfunction in Obesity, Diabetes and Atherosclerosis,” with Dr. Fisher as PPG Director.
  • Dr. Fisher was awarded the National Lipid Association (NLA) Honorary Lifetime Achievement Award (2016)
  • Dr. Kathryn Moore has been selected as Chair of the ATVB Leadership Committee of the American Heart Association for 2014-2016
  • Dr. Jeffrey Berger is granted The Leon H. Charney Lecture Award in 2014 and gives the annual talk that year.
  • Dr. Edward Fisher honored as George Lyman Duff Memorial Lecturer at 2013 AHA Scientific Sessions.
  • Dr. Berger’s work on platelets and aspirin as well as Dr. Moore’s work on miR-33 and HDL are featured in the 2013 Research Report. In the 2011 Research Report, the work of Dr. Moore, Dr. Fisher, and colleagues on inflammation and CVD progression is showcased.
  • Dr. Kathryn Moore is the recipient of the 2012 Jeffrey Hoeg Award.
  • Dr. Kathryn Moore selected to give The Leon H. Charney Lecture at NYU Medical Center and Annual T. Collins Lecture at Harvard Medical School, both in 2012.
  • Moore Lab trainee Katey Rayner, PhD, earned the American Heart Association/ATVB Early Career Award for Outstanding Investigator in 2010, and is granted the American Heart Association/ATVB Irvine H Page Young Investigator Research Award in 2012.
  • Dr. Edward Fisher selected to hold prestigious George Eastman Professorship at Oxford University in 2010-2011.

More New & Noteworthy in NYULMC Cardiology Research

 

Education

The Bell Program has established a number of ongoing training opportunities for highly accomplished graduate students and post-doctoral fellows alike. For more information on these please email us at BellProgram@nyumc.org.

Highly motivated MD and/or PhD postdoctoral candidates seeking careers as basic, translational or clinical cardiovascular investigators are encouraged to apply to our NIH Training Program in Cardiovascular Sciences. Click here to learn more.

 

Seminal Publications

Stein RA, Rockman CB, Adelman MA, Riles TS, Hiatt WR, Berger JS. Association between Physical Activity and Peripheral Artery Disease and Carotid Artery Stenosis in a self-referred population of 3 Million Adults. ATVB 2015;35:206-12.  PMID 25359858

Ramkhelawon B, EJ Hennessy, M Ménager, FJ Sheedy, TD Ray, A Wanschel, S Hutchison, S Oldebeken, M Geoffrion, W Spiro, G Miller, R McPherson, KJ Rayner, KJ Moore. Netrin-1 promotes adipose tissue macrophage accumulation and insulin resistance in obesity. Nature Medicine. 2014 Apr; 20(4): 377-84. PMC3981930

Duivenvoorden R, Tang J, Cormode DP, Mieszawska AJ, Izquierdo-Garcia D, Ozcan C, Otten MJ, Zaidi N, Lobatto ME, van Rijs SM, Priem B, Kuan EL, Martel C, Hewing B, Sager H, Nahrendorf M, Randolph GJ, Stroes ES, Fuster V, Fisher EA, Fayad ZA, Mulder WJ. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat Commun. 2014;5:3065. PMC4001802

Ramsey SA, Vengrenyuk Y, Menon P, Podolsky I, Feig JE, Aderem A, Fisher EA, Gold ES. Epigenome-guided analysis of the transcriptome of plaque macrophages during atherosclerosis regression reveals activation of the Wnt signaling pathway. PLoS Genet. 2014;10(12):e1004828. PMC4256277

Wanschel A, Seibert T, Hewing B, Ramkhelawon B, Ray TD, van Gils JM, Rayner KJ, Feig JE, O’Brien ER, Fisher EA, Moore KJ. Neuroimmune Guidance Cue Semaphorin 3E is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention. Arterioscler Thromb Vasc Biol. 2013 May; 33(5):  886-93. PMC3647027

Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, Moore KJ. CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation. Nature Immunology. 2013; 14: 812-20. PMC3720827

Ramkhelawon B, Yang Y, van Gils JM, Hewing B, Rayner KJ, Parathath S, Guo L, Oldebeken S, Feig JL, Fisher EA, Moore KJ. Hypoxia Induces Nertin-1 and Unc5b in Atherosclerotic Plaques:  Mechanism for Macrophage Retention and Survival. Arterioscler Thromb Vasc Biol. 2013 Jun; 33(6): 1180-8. PMC3793633

O'Brien M, Montenont E, Hu L, Nardi MA, Valdes V, Merolla M, Gettenberg G, Cavanagh K, Aberg JA, Bhardwaj N, Berger JS. Aspirin attenuates platelet activation and immune activation in HIV-infected subjects on antiretroviral therapy: A Pilot Study. JAIDS 2013;63:280-8. PMC3756489

Savji N, Rockman C, Skolnick A, Adelman MA, Riles T, Berger JS. Association between Advanced Age and Vascular Disease in Different Arterial Territories: A Population Database of Over 3.6 Million Subjects. J Am Coll Cardiol 2013;61(16):1736-43. PMID 23500290

Moore KJ, Sheedy FJ and Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nature Rev Immunol. 2013; Oct 13 (10): 709-21. PMC4357520

Berger JS, Becker RC, Kuhn C, Helms MJ, Ortel TL, Williams R. Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation. Thromb Haemost. 2013;109:85-92. PMC3582386

Chen W, Cormode DP, Vengrenyuk Y, Herranz B, Feig JE, Klink A, Mulder WJ, *Fisher EA, Fayad ZA (co-corresponding authors). Collagen-specific peptide conjugated HDL nanoparticles as MRI contrast agent to evaluate compositional changes in atherosclerotic plaque regression. JACC Cardiovasc Imaging. 6(3):373-84, 2013 PMC3653172

van Gils JM, Derby, MC, Fernandes LR, Ramkhelawon B, Ray TD, Rayner KJ, Parathath S, Distel E, Feig JL, Alvarez-Leite JI, Rayner AJ, McDonald TO, O’Brien KD, Stuart LM, Fisher EA, Lacy-Hulbert A, & Moore KJ. The neuroimmune guidance molecule netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nature Immunology. 2012; 13(2): 136-43. PMC22231519

Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J. Clin. Invest. 2011; 121(7): 2921-31. PMC3223840

Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE** & Moore KJ**. Inhibition of miR-33a/b in non-human primates raises plasma HDL and reduces VLDL triglycerides. Nature. 2011; 478(7369): 404-7. PMC22012398

Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, Liu J, Rayner K, Moore K, Garabedian M, Fisher EA. HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc. Natl. Acad. Sci. U S A. 108(17):7166-71, 2011 PMC3084076.

Stewart CR, LM Stuart, K Wilkinson, JM van Gils, J Deng, A Halle, KJ Rayner, L Boyer, R Zhong, WA Frazier, A Lacy-Hulbert, JB El Khoury, DT Golenbock, KJ Moore. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunology. 2010; 11(2): 155-61.  PMC2809046.

Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ & Fernández-Hernando C. miR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010; 328(5985): 1570-3. PMC3114628

Skajaa T, Cormode DP, Falk E, Mulder WJ, Fisher EA, Fayad ZA. High-Density Lipoprotein–Based Contrast Agents for Multimodal Imaging of Atherosclerosis. Arterioscler Thromb Vasc Biol. 30(2):169-76, 2010 PMC2826843

Pan M, Maitin V, Parathath S, et al. Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: a pathway for late-stage quality control. Proc Natl Acad Sci USA. 2008;105(15):5862-7. PMC2311371

Brodsky, JL, and Fisher, EA. The many intersecting pathways underlying apolipoprotein B secretion and degradation. Trends Endocrinol Metab. 2008 Sep;19(7):254-9. PMC3216472

Frias JC, Ma Y, Williams KJ, Fayad ZA, Fisher EA. Properties of a versatile nanoparticle platform contrast agent to image and characterize atherosclerotic plaques by magnetic resonance imaging. Nano Lett. 2006;6(10):2220-4. (cover article) PMID 17034087

Pan M, Cederbaum AI, Zhang YL, Ginsberg HN, Williams KJ, Fisher EA. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J Clin Invest. 2004;113(9):1277-87. (with commentary) PMC398425

Trogan E, Choudhury RP, Dansky HM, Rong JX, Breslow JL, Fisher EA. Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice. Proc Natl Acad Sci USA. 2002;99(4):2234-9. PMC122348

Rong J, Li J, Reis ED, Choudhury RP, Dansky HM, Elmalem V, Fallon JT, Breslow JL, Fisher EZ. Remodeling of advanced atherosclerotic lesions in apolipoprotein E-deficient mice by elevation of HDL cholesterol levels. Circulation, 2001;104:2447-2452. (with commentary)

Fisher EA, Zhou M, Mitchell DM, Wu X, Omura S, Wang H, Goldberg AL, Ginsberg HN.  The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteasome pathway and involves heat shock protein 70. J. Biol. Chem., 1997; 272:20427-20434. PMID: 9252351

Williams KJ, Brocia RW, Fisher EA.  The unstirred water layer as a site of control of apolipoprotein B secretion. J. Biol. Chem., 1990; 265: 16741-16744. PMID: 2170353

 

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