Phone: (706) 721-1946

Fax: (706) 721-9799

Email: dfulton@mcg.edu

Office: 3316A / Lab: 3316

Grant Support as Principal Investigator | Current Projects | Lab | Honors & Awards | Invited Speaker | Selected Publications |

Our primary research goals are to study the molecular mechanisms regulating the function of the vascular endothelium in both health and disease. More specifically, we are interested in the regulation of the enzyme endothelial nitric oxide synthase (eNOS) and its ability to produce the labile gaseous second messenger, nitric oxide. The activity of eNOS is tightly controlled and is influenced by a number of post-translational mechanisms including protein-protein interactions, phosphorylation and subcellular targeting. Within endothelial cells eNOS resides at both the peri-nuclear Golgi complex and the plasma membrane. Although numerous studies have shown that the active pool of eNOS resides in plasma membrane organelles such as caveloae and lipid rafts, we have recently demonstrated that the Golgi pool of eNOS is indeed active. We are currently studying the mechanisms regulating the activity of the Golgi eNOS and its contribution to endothelial cell function.

Diabetes and other cardiovascular diseases are associated with dysfunction or reduced activity of the endothelium. In particular, the ability of the endothelium to produce biologically active NO is compromised. We are actively involved in studies to identify the molecular mechanisms by which diabetes and insulin resistance reduce the synthesis of nitric oxide.



Confocal microscopy of subcellular localization of eNOS

American Heart Association Scientist Development Grant "Regulation of Endothelial Nitric Oxide Synthase by Subcellular Targeting." - Active: 2002-2006

NIH R01 -" Regulation of Endothelial Nitric Oxide Synthase by Subcellular Targeting." - Active 2003-2007

Title: Contribution of PI-3 Kinase and Akt to Endothelial Nitric Oxide Production.
Principal Investigator: David Fulton, Ph.D.
Agency: NIH
Type: F32
Funding Period: April 1, 1999 to March 30, 2002.
Objectives: The objective of this grant was to determine the influence of PI-3 kinase and Akt to growth factor induced NO production in endothelial cells. There is no overlap with the current project.

Title:Regulation of endothelial nitric oxide synthase by subcellular targeting
PI: David Fulton, Ph.D. % Effort: 30%
Agency: American Heart Association (National)
Type: Scientist Development Grant
Funding Period: Jan 1, 2003 to Dec 31, 2006. Direct costs $260,000
Objectives: The overall goal of this proposal is to determine the impact of intracellular location on the function of endothelial nitric oxide synthase. Relinquished due to overlap with NIH grant.

Title: Regulation of endothelial nitric oxide synthase by subcellular targeting
PI: David Fulton, Ph.D. % Effort: 40%
Agency: NIH
Type: R01 HL074279-01
Period: July, 2003 to June, 2008.
Funding Requested: Yearly: $200,000 (225,000 first year). Direct Costs Total: $1,025,000. Indirect Costs $430,000
Objectives: The overall goal of this proposal is to determine the impact of intracellular location on the function of endothelial nitric oxide synthase.

Title: Nitric Oxide and Compensatory Coronary Vasodilation
PI: David W. Stepp, Ph.D.
Agency: NIH
Type: R01
Funding Period: October 1, 2001 to September 30, 2005.
Objectives: The objective of this grant is to determine the long term effects of abrogated NO production on coronary physiology. The goal is to assess what changes occur in coronary vasodilator control (assessed both in vivo and in vitro) and what the mechanisms of these changes may be using molecular biological techniques. There is no overlap with the current project.
Role: Co-Investigator (10%)

Title: Renal Control of Blood Pressure in Early Diabetes
PI: Michael Brands, Ph.D.
Agency: NIH
Type: R01 HL075625-01
Funding Period: Feb 1, 2004 to January 31, 2008.
Objectives: Test the central hypothesis that nitric oxide counteracts angiotensin II-dependent, superoxide-mediated renal vasoconstriction during hyperglycemia early in diabetes.
Role: Co-Investigator (10%)

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(from a total of 45)

El-Remessy AB, Bartoli M, Platt DH, Fulton D, Caldwell RB. Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration. J Cell Sci. 2005 Jan 1;118(Pt 1):243-52.

Fulton D, Harris MB, Kemp BE, Venema RC, Marrero MB, Stepp DW. Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90. Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2384-93. Epub 2004 Dec.

Fulton D, Babbitt R, Zoellner S, Fontana J, Acevedo L, McCabe TJ, Iwakiri Y, Sessa WC. Targeting of endothelial nitric-oxide synthase to the cytoplasmic face of the Golgi complex or plasma membrane regulates Akt- versus calcium-dependent mechanisms for nitric oxide release. J Biol Chem. 2004 Jul 16;279(29):30349-57. Epub 2004 May 10.

Marrero MB, Fulton D, Stepp D, Stern DM. Angiotensin II-induced insulin resistance and protein tyrosine phosphatases. Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2009-13. Epub 2004 Jul 22.

Fulton D, Papapetropoulos A, Lin MI, Fontana J, McCabe TJ, Zoellner S, Garcia-Cardena G, Zhou Z, Gratton JP, Sessa WC. Vanadate is a potent activator of endothelial nitric-oxide synthase: evidence for the role of the serine/threonine kinase Akt and the 90-kDa heat shock protein. Mol Pharmacol. 2004 Feb;65(2):407-15.

Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P, Strittmatter SM, Sessa WC. A new role for Nogo as a regulator of vascular remodeling. Nat Med. 2004 Apr;10(4):382-8. Epub 2004 Mar 21.

Lin MI, Fulton D, Babbitt R, Flemming I, Busse R, Pritchard KA Jr, Sessa WC. Phosphorylation of threonine 497 in endothelial nitric oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. J Biol Chem. 2003 Sep 2 [Epub ahead of print].

Sowa G, Pypaert M, Fulton D, Sessa WC. The phosphorylation of caveolin-2 on serines 23 and 36 modulates caveolin-1-dependent caveolae formation. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6511-6. Epub 2003 May 12.

Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H, Sessa WC. Related Articles, Links Abstract Compensatory phosphorylation and protein-protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric-oxide synthase. J Biol Chem. 2003 Apr 25;278(17):14841-9.

Fulton D, Fontana J, Chen Y, Fairchild TA, McCabe TJ, Fujita N, Tsuruo T, Sessa WC. Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release. Circ Res. 2002 May 3;90(8):866-73.

Scotland RS, Morales-Ruiz M, Chen Y, Yu J, Rudic RD, Fulton D, Gratton JP, Sessa WC. Functional reconstitution of endothelial nitric oxide synthase reveals the importance of serine 1179 in endothelium-dependent vasomotion. Circ Res. 2002 May 3;90(8):904-10.

Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa WC. Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J Biol Chem. 2001 Aug 10;276(32):30359-65.

Fulton D, Fontana J, Sowa G, Gratton JP, Lin M, Li KX, Michell B, Kemp BE, Rodman D, Sessa WC. Localization of endothelial nitric-oxide synthase phosphorylated on serine 1179 and nitric oxide in Golgi and plasma membrane defines the existence of two pools of active enzyme. J Biol Chem. 2002 Feb 8;277(6):4277-84.

Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn't calcium/calmodulin enough? J Pharmacol Exp Ther. 2001 Dec;299(3):818-24. Review.

Fairchild TA, Fulton D, Fontana JT, Gratton JP, McCabe TJ, Sessa WC. Acidic hydrolysis as a mechanism for the cleavage of the Glu(298)-->Asp variant of human endothelial nitric-oxide synthase. J Biol Chem. 2001 Jul 13;276(28):26674-9.

Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000 Sep;6(9):1004-10.

Luo Z, Fujio Y, Kureishi Y, Rudic RD, Daumerie G, Fulton D, Sessa WC, Walsh K. Acute modulation of endothelial Akt/PKB activity alters nitric oxide-dependent vasomotor activity in vivo. .J Clin Invest. 2000 Aug;106(4):493-9.

Rudic RD, Bucci M, Fulton D, Segal SS, Sessa WC. Temporal events underlying arterial remodeling after chronic flow reduction in mice: correlation of structural changes with a deficit in basal nitric oxide synthesis. Circ Res. 2000 Jun 9;86(11):1160-6.

Fulton D, Papapetropoulos A, O'Connor D, Li F, Mahboubi K, Altieri D, Sessa WC. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem. 2000 Mar 31;275(13):9102-5.

McCabe TJ, Fulton D, Roman LJ, Sessa WC. Enhanced electron flux and reduced calmodulin dissociation may explain "calcium-independent" eNOS activation by phosphorylation. J Biol Chem. 2000 Mar 3;275(9):6123-8.

Morales-Ruiz M, Fulton D, Sowa G, Languino LR, Fujio Y, Walsh K, Sessa WC. Vascular endothelial growth factor stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ Res. 2000 Apr 28;86(8):892-6.

Fulton D., Papapetropoulos A, Zhang X, Catravas JD, Hintze TH, Sessa WC. Quantification of eNOS mRNA in the canine cardiac vasculature by competitive PCR. Am J Physiol Heart Circ Physiol 2000 ;278(2):H658-65.

Oyekan AO, Youseff T, Fulton D., Quilley J, McGiff JC. Renal cytochrome P450 omega-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride. J Clin Invest 1999 Oct;104(8):1131-7.

Fulton D., Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999 Jun 10;399(6736):597-601.

Post Doctoral Training, Yale University, CT 1997-2002.
Pharmacology

Ph.D., New York Medical College, NY 1996.
Pharmacology

M.S., New York Medical College, NY 1994.
Pharmacology

B.Sc., Monash University, Melbourne, Austraila 1991.
Pharmacology (Honors)

1997-2002.Research Associate, Pharmacology. Yale University, New Haven, CT.

2002-Present. Assistant Professor, Pharmacology. Medical College of Georgia, GA

• 1999-Present, Sigma Xi.
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• 2002-Present, American Physiological Society.
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• 2003-Present, American Heart Association Council for High Blood Pressure Research,