PHA/ATS Partnership Grant Winner 2006

Todd Bull, MDTodd Bull, MD

University of Colorado
“The role of Kaposi’s sarcoma herpesvirus in the development of severe pulmonary hypertension”

Term: January 1, 2006 – December 31, 2007

Summary of Research Project:

The role of Kaposi’s sarcoma herpesvirus in the development of severe pulmonary hypertension

 Severe pulmonary arterial hypertension (PAH) is a poorly understood disease with devastating clinical consequences to those afflicted. The disease process of PAH is characterized by an abnormal growth of cells in the pulmonary arteries. The endothelial and smooth muscle cells of the small, pre-capillary pulmonary vasculature proliferate in an uncontrolled fashion, forming the pathologic structure referred to as the “plexiform lesion”. The plexiform lesion manifests a number of characteristics of a cancer including unregulated cell growth. The cells of the plexiform lesion eventually obstruct the pulmonary artery lumen, inhibiting blood flow through the lung. We have recently reported evidence of Human Herpesvirus-8 (HHV-8) infection in the plexiform lesions of patients with idiopathic pulmonary arterial hypertension (IPAH). HHV-8 is a recognized cause of the cancer Kaposi’s sarcoma and is associated with a number of other malignancies. HHV-8 is known to infect endothelial cells and is believed to cause abnormal growth of these cells. In this grant application we propose to investigate mechanisms by which HHV-8 contributes to the development of severe pulmonary hypertension. We have demonstrated the ability of HHV-8 to infect pulmonary microvascular endothelial cells. We will now investigate the effect of this infection on the gene and protein expression of these cells as well as the effect on cell growth and cell apoptosis (programmed cell death). We will also explore a possible connection between HHV-8 infection and alterations in the bone morphogenic protein (BMP) pathway, a pathway recognized to be important in the development of pulmonary hypertension.

Curriculum Vitae

  • Purdue University, 1986, Biology
  • Northwestern University, B.A., 1987-90, Biochemistry and Molecular Biology
  • University of Colorado, M.D., 1990-94 Medicine
  • University of Texas, Southwestern, 1994-97, Internal Medicine Residency
  • University of Colorado, 1999-2002, Pulmonary/Critical Care 

Fellowship Positions and Honors

  • 1987 Gables Club Award for Academic Excellence.
  • 1988-89 Accepted for Honors Program in Medical Research, MD Anderson Cancer Center.
  • 1990-94 Elected to the University of Colorado Student Senate.
  • 1990-92 Academic Excellence Awards for MS-I and MS-II years, University of Colorado School of Medicine
  • 1994 Graduated with Honors, University of Colorado School of Medicine.
  • 1994 Elected to Alpha Omega Alpha Medical Honor Society.
  • 1994-97 Residency, Internal Medicine. U.T. Southwestern Medical Center, Dallas TX.
  • 1998 Faculty, Department of Internal Medicine, St. Josephs Hospital, Denver CO.
  • 1999-02 Pulmonary/Critical Care Fellow, University of Colorado Health Sciences Center.
  • 2000-Present Medical School Admissions Committee, University of Colorado School of Medicine.
  • 2002-Present Scholarship Committee, University of Colorado School of Medicine.
  • 2002-Present Residency Selection Committee, University of Colorado School of Medicine.
  • 2000-2002 Pulmonary Hypertension Association Postdoctoral Fellowship Award administered through the American Heart Association.
  • 2002-2004 Clinical Instructor, Pulmonary and Critical Care division, University of Colorado School of Medicine.
  • 2003-2004 Will Rodgers Fellow, Pulmonary and Critical Care division, University of Colorado School of Medicine
  • 2003-Present Medical ICU Quality Initiative Committee, University Hospital, Denver Colorado
  • 2004-Present University Hospital ICU oversight committee, University Hospital, Denver Colorado.
  • 2004-Present Assistant Professor of Medicine, University of Colorado School of Medicine.
  • 2004-Present Editorial Board “Advances in Pulmonary Hypertension”.
  • 2005-Present Medical Director Fitzsimons Medical Center, Intensive Care Unit.
  • 2005-Present Scientific Leadership Council (SLC) of the Pulmonary Hypertension Association.
  • 2006 Mark Flapan award: Awarded annually to the best research proposal submitted to the Scleroderma Foundation.
  • 2006 Department of Medicine Housestaff teaching award. 

Journal Referee

  • 2004-present: Clinical Chemistry and Laboratory Medicine
  • 2005-present: American Journal of Respiratory and Critical Care Medicine

Grant Review Referee

  • 2005-present: Health Research Board of Ireland

Other Published Articles

  1. Bull, TM. Cool, C.D., Campbell, T.B., Neid, J.M., Voelkel, N.F., Badesch, D.B. Primary pulmonary hypertension, Castleman’s disease and human herpesvirus-8. Eur Respir J 2003;22: 403-407
  2. Bull, TM. Golpon, H. Moore, M. Hebbel, P. Cool, C. Tuder, R., Geraci, M. Voelkel, N. Circulating Endothelial Cells in Pulmonary Hypertension. Thromb Haem 2003:90:698-703.
  3. Cool, C.D., Rai, P.R., Yeager, M.E., Serls, A.E., Bull, T.M., Geraci, M.W., Brown, K.K., Routes, J.M., Tuder, R.M., Voelkel, N.F. Expression of Human Herpesvirus 8 in Primary Pulmonary Hypertension. N Engl J Med 2003;349:1113-22
  4. Bull, TM. Fagan, KA., Badesch, DB. Pulmonary Hypertension: The Latest Treatments. J Respir Dis. 2004;25(6):242-245.
  5. Bull, TM. Coldren, CD. Moore, M. Sotto-Santiago, S. Pham, DV. Nana-Sinkam, SP. Voelkel, N.F. Geraci MW. Gene Microarray Analysis of Peripheral Blood Cells in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2004 Jun 23.
  6. Bull TM, Fagan KA, Badesch DB, Pulmonary Vascular Manifestations of Mixed Connective Tissue Disease. Rheum Dis Clin North Am 2005 Aug, 31(3) 451-64
  7. Bull, TM. New and Future Therapies in Pulmonary Arterial Hypertension. Semin Respir Crit Care Med 2005 Aug;26(4):429-36
  8. Bull, TM. Physical Examination in Pulmonary Arterial Hypertension. Adv in Pulm Htn. 2005; 4(3) 6-10.
  9. Bull TM, Coldren CD, Nana-Sinkam P, Sotto-Santiago S, Moore M, Voelkel NF, Geraci, MW. Microarray analysis of peripheral blood cells in pulmonary arterial hypertension, surrogate to biopsy. Chest 2005 Dec;128(6 Suppl):584s.
  10. Fagan KA, Bull TM, Badesch DB, Voelkel NF. Metastatic cancer while receiving continuous prostacyclin therapy. Chest 2005 Dec, Dec;128(6 Suppl):619s-620s
  11. Bull TM, Coldren CD, Geraci MW, Voelkel NF Gene Expression Profiling in Pulmonary Hypertension Proc Am Thorac Soc 2006 pending publication

Abstracts:

  1. Bull, TM., Tuder, R., Voelkel, N., Circulating Endothelial Cells in Primary Pulmonary hypertension. Presented at ATS, San Diego. Amer J Resp Crit Care Med.
  2. Bull, TM., Moore, M., Shepherd, D., Tuder, M., Voelkel, N., Geraci, M., Microarray Expression Analysis of Circulating Human Endothelial Cells in Patients with Pulmonary Hypertension. Presented at AHA, New Orleans. Circ. 102(18), 479, 2000.
  3. Bull, TM., Geraci, M., Golpon, H., Moore, M., Cleary, K., Tuder, R., Voelkel, N., Phenotypic and Genotypic Evaluation of Circulating Endothelial Cells in Patients with Primary Pulmonary Hypertension. Presented at ATS, San-Francisco. Amer J Resp Crit Care Med. 163(5) A404, 2001.
  4. Bull, TM., Moore, M., Geraci, M., Voelkel, N., The Microarray Gene Expression Profile of Peripheral Blood is Altered in Patients with PPH. Presented at the 2002 AHA Asia Pacific Scientific Forum/42nd Annual Conference on Cardiovascular Disease Epidemiology and Prevention.
  5. Bull, TM., Cool, D., Campbell, T, Pradeep, R., Serl, A., Neid, J., Voelkel, N. Badesch, D. HHV-8 as a Potential Trigger Factor for the Development of Primary Pulmonary Hypertension. Presented at the World Symposium on Pulmonary Arterial Hypertension. Venice, Italy. June, 2003.
  6. Bull, TM. Coldren, C. Moore, M. Voelkel, N. Geraci, M. Microarray Analysis of Peripheral Blood Mononuclear Cells in Severe Pulmonary Hypertension. Presented at the World Symposium on Pulmonary Arterial Hypertension. Venice, Italy. June, 2003.
  7. Bull, TM. Coldren, C. Moore, M. Sotto-Santiago, S. Pham, D. Nan-Sinkam, P. Voelkel, N, Geraci, M. Microarray Expression of Peripheral Blood Cells in Severe Pulmonary Hypertension, Insight into Pathobiology and a Potential Diagnostic Test. Presented at ATS, Orlando.June 2004. Amer J Resp Crit Care Med.

 Read Dr. Bull's story

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