PHA/NHLBI K08/K23 Award Winner 2008

Daniel Greif, MDDaniel M. Greif, MD

Section of Cardiovascular Medicine
Yale University, School of Medicine
"Morphogenesis of the Pulmonary Artery Smooth Muscle Layer"
NHLBI Mentored Clinical Scientist Development Award (K08)
August 1, 2009 - July 31, 2013

Summary of Research Project:

"Morphogenesis of the Pulmonary Artery Smooth Muscle Layer"

During artery development, little is known about how concentric layers of smooth muscle cells and the outer adventitial layer are assembled and patterned around the inner endothelial tube. In this project, we show that the pulmonary artery wall in the mouse is constructed radially, from the inside out, by two separate but coordinated processes. One is sequential building of successive cell layers from surrounding cells. The other is controlled invasion of outer layers by inner layer cells through strictly regulated cell reorientation and radial migration. We propose that a radial signal gradient controls these processes and provides evidence that the platelet derived growth factor-B and at least one other signal contribute.

Many serious vascular diseases, such as pulmonary hypertension, involve altered size and structure of the arterial wall, and elucidating how arterial walls are built could aid understanding of these diseases. Our studies indicate that during normal development, the pulmonary artery wall is built radially, from the inside out, and that this construction is regulated by gradients of signaling molecules. Alterations of such radial signaling pathways may underlie pathological changes in the wall structure of large caliber arteries and the distal arteriole muscularization in the pulmonary vasculature during pulmonary hypertension. Attenuating these aberrant signaling gradients may provide novel approaches for combating pulmonary hypertension.

Curriculum Vitae

Daniel M. Greif, MD
Assistant Professor of Medicine, Yale University School of Medicine

EDUCATION AND TRAINING

Institution and Location Degree Year Field of Study
Stanford University
Stanford, Calif.
BS 1991 Chemical Engineering
University of California
San Francisco, Calif.
MD with Thesis 1997 Medicine


POSITIONS AND HONORS

Positions and Employment

10/95-9/96 Sarnoff Cardiovascular Research Foundation Fellow, Vascular Research Division, Department of Pathology, Harvard Medical School, Brigham & Women's Hospital. Boston, MA. Laboratory of F. William Luscinskas, PhD (Between 3rd and 4th year of medical school)
6/97-6/99 Intern and Junior Resident, Dept of Internal Medicine, University of Washington, Seattle, WA.
7/99-6/00 Senior Resident, Dept of Internal Medicine, Brigham & Women’s Hospital, Boston, MA.
7/00-6/03 Howard Hughes Medical Institute Physician Postdoctoral Research Fellow, Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital. Boston, MA. Laboratory of Thomas Michel, MD, PhD
7/03-6/07 Cardiology Fellow (clinical), Cardiovascular Med Division, Stanford University, Stanford, CA.
7/05-7/08 Postdoctoral Research Fellow, Howard Hughes Medical Institute and Department of Biochemistry, Stanford University School of Medicine, Stanford, CA. Laboratory of Mark Krasnow, MD, PhD
8/08-9/10 Instructor, Department of Biochemistry, Stanford University School of Medicine, Stanford, CA. Laboratory of Mark Krasnow, MD, PhD
10/10- Assistant Professor of Internal Medicine, Cardiovascular Section, Yale University School of Medicine, New Haven, CT.


Grant Reviewer, Clinical Activity and Professional Memberships

1995- Member, Society of Fellows, Sarnoff Cardiovascular Research Foundation
1997- Member, North American Vascular Biology Organization
2000 Diplomate, Internal Medicine, American Board of Internal Medicine
2006 Diplomate, Cardiovascular Medicine, American Board of Internal Medicine
2007 Attending, Cardiology Consult Service, Stanford University
2008 Attending, Cardiology Clinic, Stanford University
2011- Attending, Cardiology Consult Service, Yale University
2011- Attending, Cardiology Clinic, Yale University
2011, 2013- Reviewer, American Heart Association’s Molecular Signaling 4 Peer Review Study Group
2012 Reviewer, Wellcome Trust Research Grants
2013 Reviewer, NIH/NHLBI Grants, Special Emphasis Panel


Honors and Awards

1988 Cold Spring Harbor Laboratory Undergraduate Summer Research Award
1990 International Association for Student Exchange for Technical Experience Fellowship
1995 Angiogenesis Foundation Fellowship
1995-1996 Sarnoff Cardiovascular Research Foundation Fellowship
1997 UCSF MD with Thesis
2000-2003 Howard Hughes Medical Institute Physician Postdoctoral Research Fellowship
2005-2009 Sarnoff Cardiovascular Research Foundation Scholar Award
2006 Gerald Reaven Stanford Cardiology Fellow Excellence in Laboratory Research Award
2007 Finalist, Burroughs Wellcome Foundation Career Award for Medical Scientists
2009-2010 Stanford University Child Health Research Program Pilot Early Career Award
2008-2013 NIH/NHLBI K08 Award
2008-2013 Pulmonary Hypertension Association Clinical Scientist Development Award
2012-2014 Yale Center for Clinical Investigation Scholar Award
2013 Invited Presentation, Gordon Research Conference entitled Elastin, Elastic Fibers & Microfibrils
2013-2015 Basil O’Connor Starter Scholar Award, March of Dimes Foundation


RESEARCH PUBLICATIONS

Original Research

Greif, DM*, Goetz, DJ*, Ding, H, Camphausen, RT, Howes, S, Comess, KM, Snapp, KR, Kansas, GS, Luscinskas, FW. (1997). Isolated PSGL-1 dynamic adhesion to P- and E-selectin. Journal of Cell Biology, 137(2): 509-519. PMC2139768. (*Authors contributed equally and are listed alphabetically on publication).

Greif, DM. P-selectin glycoprotein ligand-1 mediated adhesion to P- and E-selectin under flow [M.D. with thesis]. San Francisco (CA): University of California, San Francisco; 1997.

Kou, R, Greif, D, Michel, T. (2002). Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. Journal of Biological Chemistry, 277:29669-73.

Greif, DM, Kou, R, Michel, T. (2002). Regulation of eNOS dephosphorylation by protein phosphatase 2A: evidence for crosstalk between phosphorylation sites. Biochemistry, 41:15845-53.

Greif, DM, Sacks, DB, Michel, T. (2004). Calmodulin phosphorylation and modulation of endothelial nitric oxide synthase catalysis. Proceedings of the National Academy of Sciences, 101: 1165-1170. PMC337024.

Banerjee, SS, Lin, Z, Atkins, GB, Greif, DM, Rao, RM, Feinberg, MW, Chen, Z, Simon, DI, Luscinskas, FW, Michel, TM, Garcia-Cardena, G, Gimbrone, MA, Jain, MK. (2004). KLF2 is a novel transcriptional regulator of proinflammatory activation. The Journal of Experimental Medicine, 199:1305. PMC2211816.

London, NR, Zhu, W, Bozza, FA, Smith, MC, Greif, DM, Sorensen, LK, Chen, L, Kaminoh, Y, Chan, AC, Passi, SF, Day, CW, Barnard, DL, Zimmerman, GA, Krasnow, MA, Li, DY. (2010). Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza. Science Translational Medicine, 2 23ra19:1-10. PMC2875996.

Greif, DM*, Kumar, M, Lighthouse, JK, Hum, J, An, A, Ding, L, Red-horse, K, Espinoza, FH, Olson, L, Offermanns, S, Krasnow, MA*. (2012). Radial construction of an arterial wall. Developmental Cell, 23:482. PMC3500096. (*Corresponding authors).

Kim, J, Kang, Y, Kojima, Y, Lighthouse, JK, Hu, X, Aldred, MA, McLean, DL, Park, H, Comhair,SA, Greif, DM, Erzurum, SC, Chun, HJ. (2013). A Novel Endothelial Apelin-FGF Link Mediated by MicroRNAs 424 and 503 is Disrupted in Pulmonary Arterial Hypertension. Nature Medicine, 19:74. PMC3540168.

Reviews and Book Chapters

Goetz, DJ, Greif, DM, Shen, J, Luscinskas, FW. Cell-cell adhesive interactions in an in vitro fluid flow assay. In: E. Dejana, M. Corada, editors. Methods in Molecular Biology. Totawa, NJ: Humana Press Inc.; 1997. p. 137-145.

Dudzinski, DM, Igarashi, J, Greif, D, Michel, T. (2006). The regulation and pharmacology of endothelial nitric oxide synthase. Annual Review of Pharmacology and Toxicology, 46:235-76.

Greif, DM. Invited chapter: Vascular embryology and angiogenesis. In: M.A. Creager, J.A. Beckman, and J. Loscalzo, editors. Vascular Medicine, A Companion to Braunwald’s Heart Disease, 2nd edition. Philadelphia, PA: Elsevier Inc.; 2012. p. 1-13.

Seidelman, S, Lighthouse, JK, Greif, DM*. Invited review (in revision): Development and pathologies of the arterial vascular wall. Cellular and Molecular Life Sciences. (*Corresponding author).

RESEARCH SUPPORT

Active

8/1/08 – 7/31/13 1K08HL093362-01 (PI, Greif)
NIH/NHLBI
Morphogenesis of the pulmonary artery smooth muscle cell layer
The major goal of the proposed research is to elucidate the key steps in the morphogenesis of the vascular smooth muscle cell layer of the murine pulmonary artery during early lung development.
8/1/08 – 7/31/13 Clinical Scientist Development Award (PI, Greif)
Pulmonary Hypertension Association
Morphogenesis of the pulmonary artery smooth muscle cell layer
This award supplements the support for the K08 project described above.
7/1/12 – 6/30/14 Scholar Award (PI, Greif)
Yale Center for Clinical Investigation
The role of interleukin-6 in human and rodent pulmonary hypertension
The overall goal of this proposal is to elucidate the roles of interleukin-6 signaling in tissues or cells isolated from human patients with pulmonary hypertension or controls and in mice with interleukin-6-induced pulmonary hypertension.
2/1/13 – 1/31/15 Basil O’Connor Starter Scholar Award (PI, Greif)
March of Dimes Foundation
Excessive and ectopic vascular smooth muscle cells in pulmonary hypertension: from where do they come and how they get here?
The major objective of this proposal is to determine the origin and clonal relationship of the excess SMCs in the hypoxia/vascular endothelial growth factor inhibition mouse model of pulmonary hypertension.
7/1/13 – 6/30/14 Brown-Coxe Postdoctoral Fellowship (PI, Misra; Mentor, Greif)
Yale University School of Medicine
(This grant was awarded to Dr. Ashish Misra to support his postdoctoral research in the Greif laboratory.)
Clonal nature of aortic wall in development and disease
This project aims to determine the clonal nature, origin and recruitment of aortic wall progenitors in wild type and elastin mutant mice as well as the role of beta integrins in hypermuscularization of the elastin mutant aorta.
7/1/13 – 6/30/14 Senior Research Fellowship RT-271901 (PI, Sheikh; Mentor, Greif)
American Lung Association (probable renewal available for one additional year)
(This grant was awarded to Dr. Abdul Sheikh to support his postdoctoral research in the Greif laboratory.)
Origins of excess smooth muscle cells and PDGF in pulmonary hypertension
The major goal of this proposal is to study the role of PDGF in recruitment of excess smooth muscle in pulmonary hypertension.


Completed

7/1/09 – 6/30/10 Pilot Early Career Award (PI, Greif)
Pediatric Research Fund
Child Health Research Program, Stanford University
Circumferential patterning of the developing pulmonary arterial wall
The major goal of this pilot award is to investigate the dynamic shape of the cells that comprise the developing pulmonary arterial wall.

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