PHA/ATS/Pfizer Research Fellowship in Pulmonary Arterial Hypertension Grant Winner 2010

Laura E. Fredenburgh, MD Laura E. Fredenburgh, MD

Brigham and Women’s Hospital
“Oncogene Mutational Profiling in Pulmonary Arterial Hypertension”
Term: September 2010 – August 2012

Summary of Research Project:

Oncogene Mutational Profiling in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by abnormal growth of cells within the pulmonary artery wall, similar to cancer cells, which may lead to irreversible vascular remodeling, failure of the right side of the heart, and death. Inherited genetic mutations in a protein called bone morphogenetic protein receptor 2 (BMPR2) have been found in 70% of familial and 20-30% of idiopathic PAH (IPAH) patients. However, the chance that an individual with a mutation develops disease is only 10-20% and most patients with IPAH do not have one of these mutations. We hypothesize that spontaneous mutations occur in cancer genes in cells within the vessel wall of pulmonary arteries and promote uncontrolled growth of cells, leading to irreversible vascular remodeling and the development of clinical disease. The goal of our proposed studies is to perform a rigorous genetic analysis of DNA isolated from PAH patients to determine if spontaneous mutations occur in genes linked to common cancers. Our research has the potential to discover new pathways for targeted therapy to prevent irreversible vascular remodeling, right heart failure, and death in patients with PAH.

Curriculum Vitae

NAME: Laura E. Fredenburgh, M.D.
POSITION TITLE: Assistant Professor of Medicine, Harvard Medical School
Associate Physician, Brigham and Women's Hospital

EDUCATION/TRAINING
INSTITUTION AND LOCATION   DEGREE   YEAR(s)   FIELD OF STUDY
Bryn Mawr College, Bryn Mawr, PA   B.A., 5/91   1987-1991   Chemistry (Honors)
Columbia University, New York, NY   M.A., 5/92   1991-1992   Chemistry
McGill University, Montreal, Quebec   M.D., 5/98   1994-1998   Medicine
Beth Israel Deaconess Medical Center,
Boston, MA
  Residency   1998-2001   Internal Medicine
Harvard Medical School, Boston, MA   Fellowship   2001-2005   Pulmonary & Critical Care

 

Positions and Honors

Positions and Employment:

  • 1998–2001 Internship and Residency, Department of Medicine, Dr. Robert C. Moellering, Beth Israel Deaconess Medical Center, Boston, MA
  • 1998–2005 Clinical/Research Fellow in Medicine, Harvard Medical School, Boston
  • 2001–2005 Fellowship, Division of Pulmonary and Critical Care Medicine, Dr. Steven D. Shapiro, Brigham and Women’s Hospital, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
  • 2002–2005 Research Fellow, Division of Pulmonary and Critical Care Medicine, Dr. Mark A. Perrella, Brigham and Women’s Hospital, Boston, MA
  • 2005–2009 Instructor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston
  • 2009–present Assistant Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston

Certification

  • 2001 Diplomate of American Board of Internal Medicine
  • 2004 Diplomate of American Board of Internal Medicine – Pulmonary Disease
  • 2005 Diplomate of American Board of Internal Medicine – Critical Care Medicine

Honors and Awards

  • 1989 Sherman Fairchild Grant, Bryn Mawr College
  • 1990 Pew Grant, Bryn Mawr College
  • 1991 American Chemical Society Outstanding Undergraduate Award
  • 1991 American Chemical Society Scholastic Achievement Award
  • 1991 Magna cum laude, Bryn Mawr College
  • 1995 Dr. Clarke K. McLeod Scholarship, McGill University
  • 1994–1998 Jane V. Myers Medical Scholarship, Bryn Mawr College
  • 2007–2010 Parker B. Francis Fellowship in Pulmonary Research
  • 2009–2011 NIH Clinical Research Loan Repayment Program Award

Selected Peer-reviewed Publications
 
1. Baron RM, Carvajal IM, Fredenburgh LE, Liu X, Porrata Y, Cullivan ML, Haley KJ, Sonna LA, DeSanctis GT, Ingenito EP, Perrella MA. Nitric Oxide Synthase-2 Downregulates Surfactant Protein-B Expression and Enhances Endotoxin-Induced Lung Injury in Mice. FASEB J. 2004; 18(11): 1276-1278. http://www.fasebj.org/cgi/reprint/04-1518fjev1. PMID: 15208261.

2. Baron RM, Carvajal IM, Liu X, Okabe RO, Fredenburgh LE, Macias AA, Chen Y-H, Ejima K, Layne MD, Perrella MA. Reduction of Nitric Oxide Synthase 2 Expression by Distamycin A Improves Survival from Endotoxemia. J Immunol. 2004; 173(6): 4147-4153. http://www.jimmunol.org/cgi/content/full/173/6/4147. PMID: 15356165.

3. Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD. Cyclooxygenase-2 Plays a Pivotal Role in the Resolution of Acute Lung Injury. J Immunol. 2005; 174(8):5033-5039. http://www.jimmunol.org/cgi/content/full/174/8/5033. PMID: 15814734.

4. Fredenburgh LE, Baron RM, Carvajal IM, Mouded M, Macias AA, Ith B, Perrrella MA. Absence of Heme Oxygenase-1 Expression in the Lung Parenchyma Exacerbates Endotoxin-Induced Acute Lung Injury and Decreases Surfactant Protein-B Levels. Cell Mol Biol. 2005; 51(5): 513-520. PMID: 16309574.

5. Fredenburgh LE, Perrella MA, Mitsialis SA. The Role of Heme Oxygenase-1 in Pulmonary Disease. Am J Resp Cell Mol Biol. 2007; 36(2): 158-165. doi: 10.1165/rcmb.2006-0331TR. PMCID: PMC2176110.

6. Fredenburgh LE, Campion EW, Drazen JM. Clinical Decisions. Mild Persistent Asthma–Polling Results. N Engl J Med. 2007; 357(2): 179-80. PMID: 17582063.

7. Fredenburgh LE, Liang OD, Macias AA, Polte TR, Liu X, Riascos DF, Chung SW, Schissel SL, Ingber DE, Mitsialis SA, Kourembanas S, Perrella MA. Absence of COX-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells. Circulation. 2008; 117(16): 2114-2122. PMCID: PMC2586933.

8. Takamiya R, Hung CC, Hall SR, Fukunaga K, Nagaishi T, Maeno T, Owen C, Macias AA, Fredenburgh LE, Ishizaka A, Blumberg RS, Baron RM, Perrella MA. High Mobility Group Box 1 Contributes to Lethality of Endotoxemia in Heme Oxygenase-1 Deficient Mice. Am J Respir Cell Mol Biol. 2009; 41(2): 129-35. PMCID: PMC2715902.

9. Fredenburgh LE, Ma J, Perrella MA. COX-2 Inhibition and Hypoxia-Induced Pulmonary Hypertension: Effects on Pulmonary Vascular Remodeling and Contractility. Trends Cardiovasc Med. 2009; 19(2): 31-7. PMID: 19577709. PMCID: PMC2746907.

10. Fredenburgh LE, Ma J, Englert JA, Chung SW, Liu X, Baron RM, Choi AMK, Perrella MA. Cyclooxygenase-2 Deficiency Disrupts Epithelial Tight Junction Integrity and Leads to Intestinal Barrier Dysfunction During Polymicrobial Sepsis. Submitted.

Proceedings of Meetings

1. Fredenburgh LE, Dougherty G. Potential Impact of Once-A-Day Ceftriaxone on Reducing Inappropriate Hospitalization for Pediatric Cellulitis. Presented at the 1996 Pediatric Academic Societies’ Annual Meeting, Washington, DC, May 1996. Archives of Pediatrics and Adolescent Medicine. 1996; 150 (Supp): 76.

2. Baron RM, Carvajal IM, Fredenburgh LE, Porrata Y, Haley K, Sonna LA, Layne MD, Yet S-F, Ingenito EP, Perrella MA. Nitric Oxide Synthase 2 Mediates Acute Lung Injury in Mice Through Decreased Surfactant Protein B Expression. Circulation. 2003; 108: 269. Presented at the American Heart Association Scientific Sessions 2003, Orlando, FL, November 2003.

3. Chung SW, Chen Y-H, Fredenburgh LE, Layne MD, Yet S-F, Perrella MA. Ets2 Enhances Heme Oxygenase-1 Gene Expression through an Akt-independent Phosphoinositide 3 (PI3)-Kinase Pathway. Am J Resp Crit Care Med. 2004; 169 (7): A423. Presented at the American Thoracic Society 100th International Conference, Orlando, FL, May 2004.

4. Fredenburgh LE, Ejima K, Liu X, Baron RM, and Perrella MA. Attenuation of Hypotension in COX-2 Null Mice Contributes to Improved Outcome In Endotoxemia. Am J Resp Crit Care Med. 2004; 169 (7): A636. Presented at the American Thoracic Society 100th International Conference, Orlando, FL, May 2004.

5. Baron RM, Carvajal IM, Fredenburgh LE, Liu X, Porrata Y, Haley KJ, Sonna LA, DeSanctis GT, Ingenito EP, Perrella MA. Nitric Oxide Synthase-2 Mediates Acute Lung Injury in Mice through Decreased Surfactant Protein-B Expression. Am J Resp Crit Care Med. 2004; 169 (7): A264. Presented at the American Thoracic Society 100th International Conference, Orlando, FL, May 2004.

6. Baron RM, Fredenburgh LE, Macias AA, Okabe RO, Layne MD, Perrella MA. Reduction of Nitric Oxide Synthase 2 Expression by Minor Groove Binding Agents Improves Survival from Endotoxemia. Proc Am Thorac Soc. 2005; 2: A930. Presented at the American Thoracic Society 101st International Conference, San Diego, CA, May 2005.

7. Fredenburgh LE, Ejima K, Baron RM, Chung SW, Layne MD, Perrella MA. Enhanced COX-2 Expression in HO-1 Null Mice Contributes to Endotoxemic Lung Injury. Proc Am Thorac Soc. 2005; 2: A152. Presented at the American Thoracic Society 101st International Conference, San Diego, CA, May 2005.

8. Fredenburgh LE, Liang OD, Macias, AA, Mitsialis SA, Kourembanas S, Perrella MA. Exacerbation of Hypoxia-Induced Pulmonary Hypertension and Vascular Remodeling in COX-2 deficient mice. Proc Am Thorac Soc. 2006; 3: A278. Presented at the American Thoracic Society 102nd International Conference, San Diego, CA, May 2006

9. Fredenburgh LE, Baron RM, Carvajal IM, Mouded M, Macias AA, Ith B, Perrella MA. Absence of Heme Oxygenase-1 Expression in the Lung Parenchyma Exacerbates Endotoxin-Induced Acute Lung Injury. Proc Am Thorac Soc. 2006; 3: A571. Presented at the American Thoracic Society 102nd International Conference, San Diego, CA, May 2006.

10. Fredenburgh LE, Polte TR, Liang OD, Mitsialis SA, Kourembanas S, Perrella MA. Enhanced Hypertrophy and Increased Contractility in COX-2 Deficient Vascular Smooth Muscle Cells in Response to Hypoxia. Am J Resp Crit Care Med. 2007; 175: A44. Presented at the American Thoracic Society 103rd International Conference, San Francisco, CA, May 2007.

11. Fredenburgh LE, Liang OD, Macias AA, Liu X, Riascos DF, Chung SW, Schissel SL, Mitsialis SA, Kourembanas S, Perrella MA. Role of COX-2 in Hypoxia-Induced Pulmonary Hypertension and Vascular Remodeling. Am J Resp Crit Care Med. 2008; 177: A252. Presented at the American Thoracic Society 104th International Conference, Toronto, ON, May 2008.

12. Takamiya R, Fukunaga K, Baron RM, Hung C, Ith B, Fredenburgh LE, Ishizaka A, Layne MD, Perrella MA. Circulating Levels of HMGB1 Are Exaggerated in HO-1 Null Mice during Endotoxemia. Am J Resp Crit Care Med. 2008; 177: A467. Presented at the American Thoracic Society 104th International Conference, Toronto, ON, May 2008.

13. Fredenburgh LE, Chung SW, Riascos DF, Liu X, Perrella MA. Absence of COX-2 Is Detrimental during Peritonitis-Induced Polymicrobial Sepsis. Am J Resp Crit Care Med. 2008; 177: A579. Presented at the American Thoracic Society 104th International Conference, Toronto, ON, May 2008.

14. Englert JA, Ma J, Perrella MA, Fredenburgh LE. COX-2 deficiency leads to increased intestinal epithelial permeability during peritonitis-induced polymicrobial sepsis. Am J Respir Crit Care Med. 2009; 179: A1144. Presented at the American Thoracic Society 105th International Conference, San Diego, CA, May 2009.

15. Dolinay T, Baron RM, Fredenburgh LE, Massaro AF, Lanazury R, Nakahira K, Choi AMK. Inflammasome mediators predict disease severity and mortality in patients with sepsis and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2009; 179: A4646. Presented at the American Thoracic Society 105th International Conference, San Diego, CA, May 2009.

16. Fredenburgh LE, Ma J, Englert J, Liu X, Perrella MA. COX-2 Deficiency Leads To Downregulation Of ZO-1 Expression and Increased Intestinal Epithelial Permeability During Peritonitis-Induced Polymicrobial Sepsis. Am J Respir Crit Care Med; 181: A1133. Presented at the American Thoracic Society 106th International Conference, New Orleans, LA, May 2010.

17. Fredenburgh LE, Ma J, Baron RM, Liu X, Perrella MA. Absence Of COX-2 In Bone Marrow-Derived Inflammatory Cells Exacerbates Hypoxia-Induced Pulmonary Hypertension and Vascular Remodeling. Am J Respir Crit Care Med; 181: A6332. Presented at the American Thoracic Society 106th International Conference, New Orleans, LA, May 2010.

18. Dolinay T, Baron RM, Fredenburgh LE, Massaro AF, Kim YS, Gazourian L, Lanazury R, Perrella, MA, Choi AMK. Inflammasome-activated pro-inflammatory mediators are markers of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2010; 181: A1696. Presented at the American Thoracic Society 106th International Conference, New Orleans, LA, May 2010.

19. Kim YS, Dolinay T, Baron RM, Fredenburgh LE, Massaro AF, Choi AMK. Critcal illness induces autophagic response in human blood monocytes. Am J Respir Crit Care Med; 181: A6152. Presented at the American Thoracic Society 106th International Conference, New Orleans, LA, May 2010.

Research Support

Ongoing Research Support

1. “Role of Cyclooxygenase-2-derived Prostanoids in Polymicrobial Sepsis”
5K08GM083207-03, 12/01/07 – 11/30/12
Laura E. Fredenburgh, Principal Investigator
The major goals of this project are 1) to investigate the role of COX-2-derived prostanoids in a murine model of peritonitis-induced polymicrobial sepsis; and 2) to elucidate the cell type(s) responsible for mediating the protective effects of COX-2 during peritonitis-induced polymicrobial sepsis; and 3) to determine the mechanisms by which COX-2 affords protection during sepsis.

2. “Role of Cyclooxygenase-2-derived Prostanoids in Polymicrobial Sepsis”
3K08GM083207-02S1, 9/29/09 – 8/31/11
Laura E. Fredenburgh, Principal Investigator
The goal of this Administrative Supplement is to accelerate the pace of the experiments proposed in the parent grant by hiring a new full time research technician to investigate epithelial tight junction integrity in the intestine and lung during polymicrobial sepsis and ARDS.

3. “Lipid Mediators in the Resolution of Inflammation During Sepsis”
NIH/Division of Loan Repayment/NIGMS, 7/1/09 – 6/30/11
Laura E. Fredenburgh, Principal Investigator
The major goals of this project are 1) to determine the relationship between lipoxin/lipid mediator expression and the severity of illness in patients admitted to the MICU with the systemic inflammatory response syndrome (SIRS) and sepsis compared with non-infected control patients; and 2) to elucidate the effect of lipoxin/lipid mediator expression on the inflammatory response in patients admitted to the MICU with SIRS and sepsis compared with non-infected control patients.

4. “Oncogene Mutation Profiling in Pulmonary Arterial Hypertension”
American Thoracic Society/Pulmonary Hypertension Association/Pfizer Research Fellowship in Pulmonary Arterial Hypertension, 9/1/10 – 8/31/12
Laura E. Fredenburgh, Principal Investigator

The specific aims of this project are 1) to determine if somatic oncogene and tumor suppressor gene mutations play a role in the pathogenesis of pulmonary arterial hypertension by performing a genomic analysis of plexiform vascular lesions in lung tissue from PAH patients; and 2) to investigate whether somatic mutations develop in oncogenes and tumor suppressor genes in circulating endothelial progenitor cells (EPC) isolated from patients with pulmonary arterial hypertension.

Completed Research Support

1. “Role of COX-2 in Hypoxia-Induced Pulmonary Hypertension and Vascular Remodeling”
Parker B. Francis Fellowship, 7/1/07 – 6/30/10
Laura E. Fredenburgh, Principal Investigator
The major goals of this project are 1) to characterize the role of COX-2 in the pathophysiology of hypoxia-induced pulmonary hypertension and vascular remodeling; and 2) to delineate the cellular mechanisms by which COX-2 modulates pulmonary vascular remodeling during hypoxia.

2. “Role of COX-2 in Hypoxia-Induced Pulmonary Hypertension and Vascular Remodeling”
American Lung Association Biomedical Research Grant, 7/1/07 – 6/30/09
Laura E. Fredenburgh, Principal Investigator
The major goals of this project are 1) to characterize the role of COX-2 in the pathophysiology of hypoxia-induced pulmonary hypertension and vascular remodeling; and 2) to delineate the cellular mechanisms by which COX-2 modulates pulmonary vascular remodeling during hypoxia.

3. “Integrated Training in Respiratory Research”
NIH/NHLBI Institutional Training Grant, 2T32 HL07633-21, 7/1/03 – 6/30/06
Role: Post-Doctoral Fellow, (Steven D. Shapiro, Principal Investigator)
 

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