Department Name

Peter R. Nelson M.D.

RESEARCH INTERESTS:
 

Introduction

Dr. Nelson transferred his research effort to the University of Florida College of Medicine in August 2004 with his move from the University of Massachusetts.  With this transition also came a shift in the focus of his research interest.  The overall focus of his research investigation has been the behavior of the arterial wall under the conditions of vascular injury similar to that as might be expected following balloon angioplasty and stenting.  This theme pervades his clinical, basic and now, importantly, his translational research endeavors.

During the past year, Dr. Nelson has been awarded a K23 Mentored Patient-Oriented Research Career Development Award from the NIH National Heart, Lung and Blood Institute.  This project, entitled Genomic and Proteomic Determinants of Lower Extremity Revascularization Failure represents a merger of his prior basic science research activity with his current clinical interests.  It is an important part of the overall Division research initiative that focuses on the role of inflammation and the systemic inflammatory response to the development of intimal hyperplasia and outcomes in vascular surgery.  It is also a part of a University initiative to develop a center of excellence in functional genomics and proteomics.

Current Funding/Clinical Trial Activity:

1.       Principal Investigator:  Genomic and Proteomic Determinants of Lower Extremity Revascularization Failure.  K23 Mentored Patient-Oriented Research Career Development Award. NIH/NHLBI. (# 1 K23 HL084090-01, $784,929).

2.       Principal Investigator:  CRESCENDO (Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes; #EFC5826); Sanofi-Aventis.

3.       Co-Principal Investigator:  OVER (Open Versus Endovascular Repair) of Abdominal Aortic Aneurysms Trial.  VA Cooperative Trial (#498).  National PI: Frank Lederle, MD and Julie Freischlag, MD.

4.       Co-Principal Investigator:  CORAL: Cardiovascular Outcomes in Renal Atherosclerotic Lesions.  NIH/NHLBI-sponsored multicenter randomized trial.  Co-PIs: James Caridi, MD, Gregory Vonmering, MD, Titte Srinivas, MD.

5.       Site Principal Investigator:  Zilver-PTX Drug Eluting Stent Trial for Superficial Femoral Artery Occlusion.  COOK, Incorporated, enrollment anticipated Fall 2006.

6.       Sub-Investigator:  CAPTURE (Carotid RX ACCULINK/ACCUNET Post0Approval Trial to Uncover Unanticipated or Rare Events) Post-Approval Study for RX ACCULINK Carotid Stent System and RX ACCUNET Embolic Protection System (EPS) (Protocol 04-714).  Site PI: W. Anthony Lee, MD.

7.       Sub-investigator:  GE Healthcare project Clinical Study SOV 302:  A Multicentre, Phase 3, Open-Label Study to Assess the Efficacy and Safety of 0.1 mmol/kg OMNISCANT (Gadodiamide Injection) for Magnetic Resonance Angiography (MRA) of the Aorto-iliac Arteries.  PI: Shawn Meader, MD, Co-PI: Carsten Schmalfuss, MD.

8.       Sub-investigator:  STARZ TX2Ô: Study of THORACIC Aortic Aneurysm Repair with the ZenithÒ TX2Ô TAA Endovascular Graft (IDE#G030217), COOK Incorporated.  National PI: Jon Matsumura, MD; Site PI: W. Anthony Lee, MD.

9.       Sub-Investigator:  TAG-04-01 (Thoracic Aortic Graft) Treatment of Complex Aortic Pathologies.  W.L. Gore and Associates, Incorporated.  Site PI: W. Anthony Lee, MD.

10.   Sub-Investigator:  TAG-05-02 (Thoracic Aortic Graft) Primary Treatment of Descending Thoracic Aorta Aneurysms.  W.L. Gore and Associates, Incorporated.  Site PI: W. Anthony Lee, MD.

Direction of Current Translational Research Interest:

Genomic and Proteomic Determinants of Lower Extremity Revascularization Failure

This translational initiative combines both the Division's basic science interest of inflammation and the vascular biology of the arterial wall and its clinical reputation for lower extremity revascularization into Dr. Nelson's K23 proposal.  The overall hypothesis is that the systemic inflammatory response following vascular intervention influences the local milieu responsible for vascular repair and adaptation and that this response is not uniform in all patients, but rather, is modulated by either some preoperative genomic predisposition or differential leukocyte activation in the innate immune response following injury. To test this hypothesis, a human research initiative is proposed to delineate the clinical, genomic and molecular mechanisms of lower extremity revascularization failures.  Patients undergoing lower extremity infrainguinal angioplasty and/or stent placement will be analyzed in a prospective, longitudinal clinical study to define the genomic and proteomic determinants of vascular wall response to injury.  Specifically, detailed clinical outcomes data will be coupled with rigorous molecular studies to achieve the following aims: (1) To measure clinical, functional, and quality of life outcomes following lower extremity angioplasty; (2) To determine patterns of gene expression in the peripheral blood leukocyte (total leukocyte and monocyte) populations and plasma protein concentrations prior to and following vascular injury associated with lower extremity angioplasty; and (3) To correlate adverse outcomes following lower extremity angioplasty with specific genomic and proteomic profiles reflecting the diversity and magnitude of the systemic inflammatory response.

The study protocol outlines 125 patients undergoing percutaneous lower extremity angioplasty with selective stenting followed prospectively to evaluate success of intervention based on both objective clinical and functional measurements of extremity blood flow and exercise tolerance, as well as on assessment of improvements in symptomatologic and sociopsychological endpoints using the Short Form-36 and VascuQol questionnaires.  Blood will be obtained pre-intervention, immediately post-revascularization, and at defined intervals postoperatively out to 12 months of follow-up.  Genomic analysis of total blood leukocytes and enriched peripheral blood monocytes will be obtained using the Affymetrix GeneChipT system.  Multiplex proteomic analysis of circulating inflammatory cytokines will be determined based on the Luminex platform.  Blood monocytes will be phenotyped by flow cytometric analysis.  Advanced bioinformatics approaches will then be applied to the gene expression and plasma protein results and clustering and pathway analyses will be performed to identify cell signaling and cytokine pathways whose expressions or concentrations are altered in patients with adverse outcomes.  This approach will then be extended to include an additional 125 patients undergoing open lower extremity vein bypass and another 50 patients with medical (non-surgical) management as a control peripheral vascular disease cohort.  Overall, we propose that detection of an altered immune response preoperatively or in the early postoperative period can be used to identify and even predict those patients who will go on to develop early failure of their revascularization.

Direction of Current Basic Research Interests:

Role of thrombomodulin in the vascular response to injury.

Thrombin at the site of vascular injury is a major effector of thrombosis, inflammation, and pathologic SMC physiology.  Its endogenous inhibitor, thrombomodulin (TM) is a major focus of both in vitro and in vivo experimentation in the research laboratory.  We have shown that intravenous administration of TM inhibits the arterial intimal hyperplastic reaction following balloon injury in a rabbit model.  We now look to explain this pathophysiologic observation with in depth study at the bench dissecting the physiology and biochemistry surrounding TM at the site of injury.  We have shown TM to inhibit thrombin-induced SMC proliferation and have now defined a similar role in thrombin-induced SMC migration.  TM may also, independent of thrombin, have important direct controlling effects of SMC behavior and may effect signaling from other growth factors such as PDGF.  Finally, TM appears to have a multidimensional effect by also displaying anti-inflammatory properties following balloon injury.  With SMC in culture, we are currently expanding our study of the underlying cellular signaling including G-protein coupled receptors, MAP kinase, rho kinase, and intracellular calcium mechanisms.  In both the rabbit and now a porcine animal model, we have developed more focused methods to deliver thrombomodulin locally to sites of vessel injury.  This work involves cloning the thrombomodulin gene, creating constructs for transfection of SMC both in vitro as well as in vivo, and protein engineering to create thrombomodulin with a transduction domain for direct cellular uptake following angioplasty.  At the same time, we have greatly expanded our efforts to incorporate thrombomodulin onto prosthetic graft material and stents to create improved endovascular biomaterials.

New Collaboration.  Exciting collaboration has been established with Drs. Anthony Brennan and James Schumacher in the School of Bioengineering to investigate the development of a thrombomodulin-eluting stent design.  Embedded in this project is an examination of stent surface properties that, by themselves and/or with the addition of thrombomodulin, will reduce intimal hyperplasia and enhance stent patency.  Next, through collaboration with Dr. Colleen Brophy at Arizona State University, we plan to study the role of protein transduction to deliver important biomolecules to influence SMC behavior following vascular injury.  This has implications for both animal model design and human application.  Finally, the model delineated above lends itself to the study of endless such biomolecules.  On such example involves collaboration with Roche pharmaceuticals to study the role of the immunosuppressant CellCept^® as an inhibitor of intimal hyperplasia as an adjunct to angioplasty and stenting.

Direction of Current and Future Clinical Research Interests:

Detection and management of hypercholesterolemia in patients with peripheral arterial disease.

We look to continue the design of a prospective analysis of management of hypercholesterolemia in vascular surgical patients.  Research thus far has shown that only a small percentage of patients planned to undergo peripheral vascular surgery had had their lipid profile adequately evaluated and even fewer were appropriately treated according to the National Cholesterol Education Program Guidelines.  Funding will be sought to carry out a prospective analysis and implementation of a rigorous management scheme based on this data.

Development of an exercise program for the treatment of intermittent claudication.

We have developed a structured program of exercise combined with risk factor modulation showing excellent improvement in patients with intermittent claudication.  Using data from this initial work, a comparative study will be developed at the Malcom-Randall VAMC to evaluate the relative efficacy of the treadmill, the stationary bicycle, the elliptical machine and/or swimming as the format of exercise within the program.  Funding will be sought from VA as well as societal sources to fund this endeavor.

PUBLICATIONS:

1. Huber TS, Lee WA, Nelson PR, Berceli SA, Seeger JM.  Outcome After Hypogastric Bypass and Embolization During Endovascular Aneurysm Repair, In Press, J Vasc Surg, 2006.

2. Lee WA, Nelson PR.  Sheath-assisted controlled deployment technique for Excluder bifurcated main body.  In Press, J Vasc Surg, 2006.

3. McPhee JT, Asham EA, Rohrer MJ, Singh MJ, Nelson PR, Vorhies RW, Wong G, Cutler BS.  Midterm results of treatment of traumatic thoracic aortic injuries with commercially available endografts.  Submitted, J Surg Res, 2006.

4. Feezor, RF, Nelson PR, Lee, WA, Seeger, JM, Cendan J.  Laparoscopic repair of a type II endoleak following endovascular AAA repair.  In Press, J Laparoendosc Adv Surg Tech, 2006.

5. Singh MJ, Rohrer MJ, Nelson PR, Itani MS, Cutler BS.  The benefit of complete venacavography prior to percutaneous inferior vena cava interruption.  Submitted, J Vasc Surg, 2005.

6. Hollenbeck ST, Nelson PR, Yamamura S, Faries PL, Liu B, Kent KC.  Intracellular calcium transients are necessary for platelet derived growth factor but not extracellular matrix protein induced vascular smooth muscle cell migration.  J Vasc Surg, 2004;40:351-58.

7. Li J, Singh MJ, Vasiliu C, Hendricks G, Cutler BS, Nelson PR.  Recombinant human thrombomodulin inhibits arterial neointimal hyperplasia following balloon injury.  J Vasc Surg, 2004;39:1074-83.

8. Lo C, Li J, Morris M, Vasiliu C, Rohrer MJ, Singh MJ, Cutler BS, Nelson PR.  Superior Performance of Thrombomodulin Coated Small Caliber ePTFE Grafts.  (Abstract) Journal of Surgical Research, Vol. 114 (2), pp. 263-264, 2003.

9. Cote M, Martella MB, Ligetti R, Cutler, BS, Nelson PR.  Management of Hyperlipidemia in Peripheral Vascular Disease.  J Vasc Nursing, 2003; 21:63-7.

10. Grassbaugh JA, Nelson PR, Rzucidlo EM, Schermerhorn ML, Fillinger MF, Powell RJ, Zwolak RM, Cronenwett JL, Walsh DB.  Blinded comparison of preoperative duplex ultrasound and conventional arteriography for planning tibial level revascularization.  J Vasc Surg, 2003; 37:1186-90.

11. Nelson PR, Kent KC. Nuclear microinjection of DNA into human vascular smooth muscle cells.  J Surg Res, 2002; 106:202-8.

12. Li J, Singh MJ, Nelson PR, Hendricks G, Itani M, Rohrer MJ, Cutler BS.  Immobilization of human thrombomodulin to expanded polytetrafluoroethylene.  J Surg Res, 2002; 105:200-8.

13. Proia RR, Nelson PR, Mulligan-Kehoe MJ, Wagner RJ, Kehas AJ, Powell RJ. The effect of endothelial cell overexpression of plasminogen activator inhibitor - 1 (PAI-1) on smooth muscle cell migration.  J Vasc Surg 2002;36:164-71.

14. Nelson PR, Powell RJ, Schermerhorn ML, Fillinger MF, Zwolak RM, Walsh DB, Cronenwett JL.  Early results of external iliac artery stenting combined with common femoral artery endarterectomy.  J Vasc Surg, 2002;35:1107-13.

15. Nelson PR, McEnaney PM, Callahan LA, Arous EJ.  Impact of the endovascular-assisted in situ saphenous vein bypass technique on hospital costs.  Ann Vasc Surg 2001;15:653-60.

16. Nelson PR, Powell RJ, Proia RR, Fillinger MF, Zwolak RM, Walsh DB, Cronenwett JL.  Results of endovascular superficial femoral endarterectomy.  J Vasc Surg, 2001;34:526-31.

17. Proia RR, Walsh DB, Nelson PR, Powell RJ, Fillinger MF, Zwolak RW, Cronenwett JL.  Early results of infragenicular revascularization based solely on duplex arteriography.  J Vasc Surg, 2001;33:1165-70.

18. Sturdivant AL, Labombard FE, Nelson PR, Fillinger MF, Zwolak RM.  Ultrasound-Guided Compression Versus Ultrasound-Guided Percutaneous Thrombin Injection of Postcatheterization Pseudoaneurysm: Case Study.  J Vasc Tech, 2001;25:105-8.

19. Connors JL, Walsh DB, Nelson PR, Powell RJ, Fillinger MF, Zwolak RW, Cronenwett JL.  Pedal branch artery (PBA) bypass: a viable limb salvage option.  J Vasc Surg, 2000;32:1071-9.

20. Nelson PR, Kehas AJ, Wagner RJ, Proia RR, Cronenwett JL, Powell RJ.  Smooth muscle cells alter endothelial cell regulation of smooth muscle cell migration.  Surgical Forum, 2000;51:375-7.

21. Proia RR, Nelson PR, Mulligan-Kehoe MJ, Wagner RJ, Kehas AJ, Powell RJ. Endothelial cell overexpression of plasminogen activator inhibitor - 1 (PAI-1) inhibits smooth muscle cell migration.  Surgical Forum, 2000;51:371-3.

22. Nelson PR, Arous EJ.  Endovascular in-situ bypass decreases morbidity and hospital stay following infrainguinal arterial reconstruction.  J Endovasc Ther 2000; 7:309-14.

23. Arous EJ, Nelson PR, Yood SM, Kelly JJ, Sandor A, Litwin DEM.  Hand-assisted, laparoscopic aortobifemoral bypass.  J Vasc Surg 2000;31:1142-8.

24. Nelson PR, Yamamura S, Mureebe L, Itoh H, Kent KC.  Smooth muscle cell migration and proliferation are mediated by distinct phases of activation of the intracellular messenger mitogen-activated protein kinase.  J Vasc Surg 1998;27(1):117-25.

25. Itoh H, Nelson PR, Kaiura TL, Kent KC.  Distinct signaling pathways mediate extracellular matrix protein versus PDGF induced smooth muscle cell migration.  Surgical Forum 1998;49:311-3.

26. Nelson PR, Yamamura S, Kent KC.  Platelet-derived growth factor and extracellular matrix proteins provide a synergistic stimulus for human vascular smooth muscle cell migration.  J Vasc Surg 1997;26(1):104-12.

27. Itoh H, Nelson PR, Mureebe L, Horowitz A, Kent KC.  The role of integrins in saphenous vein vascular smooth muscle cell migration.  J Vasc Surg 1997;25(6):1061-9.

28. Mureebe L, Nelson PR, Yamamura S, Kent KC.  The role of pp60 c-src in vascular smooth muscle cell migration.  Surgery 1997;122(2):138-44.

29. Harrington EO, Löffler J, Nelson PR, Kent KC, Simons M, Ware JA.  Enhancement of migration by protein kinase Ca and inhibition of proliferation and cell cycle progression by protein kinase Cd in capillary endothelial cells.  J Biol Chem 1997;272(11):7390-7.

30. Nelson PR, Yamamura S, Kent KC. Extracellular matrix proteins are potent agonists of smooth muscle migration.  J Vasc Surg 1996;24(1): 25-33.

31. Yamamura S, Nelson PR, Kent KC. The role of protein kinase C in attachment, spreading, and migration of human endothelial cells.  J Surg Res 1996;63(1):349-54.

32. Yamamura S, Nelson PR, Mureebe L, Kent KC.  Proliferation and migration of vascular smooth muscle cells are mediated by distinct signaling pathways involving phospholipase C.  Surgical Forum 1996;47:362-4.

33. Jiang B, Yamamura S, Nelson PR, Mureebe L, Kent KC.  Differential effects of platelet-derived growth factor isotypes on human smooth muscle cell proliferation and migration are mediated by distinct signaling pathways.  Surgery 1996;120(2):427-32.

34. Yamamura S, Nelson PR, Kent KC.  The role of intracellular calcium in migration of human vascular smooth muscle cells.  Surgical Forum 1995;46:386-8.