PHA/ATS Fellow Career Development in Pulmonary Arterial Hypertension Grant Winner 2012

Todd Kolb, MD, PhD

Todd Kolb, MD, PhD

Division of Pulmonary and Critical Care Medicine
Johns Hopkins University School of Medicine
Title: "Regulation of Right Ventricular Angiogenesis in Hypoxic Pulmonary Hypertension by MIF"
Term: January 15, 2013 through January 14, 2014

Summary of Research Project:

Remodeling and growth (hypertrophy) of the right ventricle (RV) allows the heart to adapt to the increased workload imposed upon it by pulmonary hypertension. In some animal models of PH, growth of new blood vessels (angiogenesis) is an important component of RV remodeling, though its regulation has not been studied. Our preliminary work shows that a small protein (MIF: macrophage migration inhibitory factor) produced by heart cells may be an important regulator of RV angiogenesis during PH. MIF appears to prevent the formation of a natural inhibitor of angiogenesis called endostatin. We are currently investigating the links between MIF, endostatin, and RV angiogenesis in mice who develop PH after chronic exposure to low oxygen levels (hypoxia). We anticipate that MIF deficiency will lead to diminished RV angiogenesis, and therefore, impaired RV adaptation to PH in this model.

Results from the these studies will significantly enhance our understanding of the regulation of RV angiogenesis and the heart’s adaptive capacity in PH. Adaptive RV remodeling helps to maintain RV function in PAH, thereby delaying symptom onset and potentially prolonging survival. By clarifying the relationship between MIF, endostatin, and RV angiogenesis, these studies may ultimately identify new biomarkers that can assist in the diagnosis of PH and evaluation of disease progression and response to treatment. Furthermore, identification of unique molecular regulators of RV angiogenesis may yield potential targets for future therapies designed to improve RV remodeling and function in PH.

Curriculum Vitae 

NAME: Todd Kolb, MD, PhD
POSITION TITLE: Post-Doctoral Fellow, Department of Medicine Johns Hopkins University School of Medicine

EDUCATION/TRAINING

INSTITUTION AND LOCATION DEGREE YEAR(S) FIELD OF STUDY

University of Maryland Baltimore County, Baltimore, Md.

BS 1997 Biological Sciences

 University of Maryland Graduate School, College Park, Md.

PhD 2003 Toxicology

 University of Maryland School of Medicine, Baltimore, Md.

MD 2005 Medicine

 Johns Hopkins Hospital, Baltimore, Md.

Internship 2005-2006 Medicine

 Johns Hopkins Hospital, Baltimore, Md.

Residency 2007-2008 Medicine

 Johns Hopkins Hospital, Baltimore, Md.

Fellowship 2008-present Pulmonary & Critical Care Medicine

PROFESSIONAL EXPERIENCE

  • 2008-present, Post-Doctoral Fellow, Department of Medicine, Johns Hopkins University School of Medicine.
  • 2009-10, Assistant Chief of Service, Department of Medicine, Johns Hopkins Hospital.

RESEARCH ACTIVITIES

Publications

  1. Kolb, TM, Chang, SH, and Davis, MA, 2002. Biochemical and morphological events during okadaic acid-induced apoptosis of Tsc2-null ERC-18 cell line.Toxicol Pathol 30 (2): 235-246.
  2. Kolb, TM, and Davis, MA, 2004. The tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) provokes a prolonged morphologic response and ERK activation in Tsc2-null renal tumor cells. Toxicol Sci 81 (1): 233-242.
  3. Kolb, TM, Duan, L, and Davis, MA, 2005. Tsc2 expression increases the susceptibility of renal tumor cells to apoptosis. Toxicol Sci 88 (2): 331-339.
  4. Damarla, M, Hasem, E, Boueiz, A, Le, A, Pae, H, Montouchet, C, Kolb, T, Simms, T, Myers, A, Kayyali, U, Faestel, M, Peng, X, Reddy, S, Damico, RL, and Hassoun PM. 2009. Mitogen activated protein kinase activated protein kinase 2 regulates actin polymerization and vascular leak in ventilator associated lung injury. PLoS One 4 (2):e4600. Epub 2009 Feb 25.
  5. Kolb, TM, and Hassoun, PM. 2012. Right ventricular dysfunction in chronic lung disease. Cardiol Clin 30 (2): 243-56.

Abstracts

  1. Kloetzel, J. A., Horich, W. T., and Kolb, T. M. 1998. A centrin-like protein is a component of a basal-body sheath in Euplotes. J Euk Microbiol, 45: 3A.
  2. Kolb, T., and Davis, M. A. 1998. Subcellular distribution of mitogen activated protein kinases and Bcl-2 during okadaic acid-induced apoptosis. Toxicological Sciences 42 (S-1):147.
  3. Kolb, TM, Carbott, DE, and Davis, MA. 2000. Comparative analysis of signal transduction proteins in tumor versus non-tumorigenic renal epithelial cells. Toxicological Sciences 54 (S-1): 407.
  4. Kolb, TM, Chang, SH, and Davis, MA. 2001. Biochemical and morphologic events during okadaic acid-induced apoptosis in the Tsc2 null ERC-18 cell line. Toxicological Sciences 60 (S-1): 76.
  5. Kolb, TM, Duan, L, and Davis, MA. 2003. Altered response of Tsc2-null renal epithelial cells to the phorbol ester TPA. Toxicological Sciences 72 (S-1): 239.
  6. Damarla, M, Kolb, T, Skirball, J, Peng, X, and Hassoun, PM. 2007. Activation of MAP kinase signaling in response to mechanical ventilation. Am J Respir Crit Care Med 175: A119.
  7. Kolb, TM, Varney, J, Hassoun, PM, and Damico, RL. 2011. Macrophage Migration Inhibitory Factor (MIF)-deficient mice are protected from right ventricular remodeling in a model of chronic hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med 183: A4971.
  8. Kolb, TM, Rafaels, N, Gao, L, Barnes, K, Girgis, R, Mathai, S, Zaiman, A, Damico, RL, and Hassoun, PM. 2011. Serum Macrophage Migration Inhibitory Factor (MIF) is increased in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 183: A1990.
  9. Kolb, TM, Donahower, B, Baddoura, P, Hamdan, O, Zaiman, A, Hassoun, PM, and Damico, RL. 2012. Right ventricular myocardial angiogenesis is abrogated in macrophage migration inhibitory factor (MIF)-deficient mice with chronic hypoxic pulmonary hypertension. Am J Respir Crit Care Med 185:A3441.
  10. Kolb, TM, Boyce, D, Rafaels, N, Gao, L, Barnes, K, Girgis, R, Mathai, S, Zaiman, A, Damico, RL, and Hassoun, PM. 2012. Macrophage Migration Inhibitory Factor (MIF) promoter polymorphisms are associated with favorable hemodynamic indices in pulmonary arterial hypertension. Am J Respir Crit Care Med 185:A1881.
  11. Kolb, TM, Donahower, B, Baddoura, P, Hamdan, O, Zaiman, A, Hassoun, PM, and Damico, RL. Macrophage migration inhibitory factor (MIF) deficiency promotes increased right ventricular endostatin expression and reduced capillary density in a model of chronic hypoxic pulmonary hypertension. Presented at the Thomas Petty Aspen Lung Conference, Aspen, CO, June 2012.
  12. Kolb, TM, Boyce, D, Lechtzin, N, Rafaels, N, Gao, L, Barnes, K, Girgis, R, Zaiman, A, Mathai, S, Hummers, L, Housten, T, Damico, RL, and Hassoun, PM. Macrophage migration inhibitory factor (MIF) promoter polymorphisms are associated with favorable hemodynamics in systemic sclerosis-associated pulmonary arterial hypertension. Presented at the European Respiratory Society Annual Meeting, Vienna, Austria, Sept 2012.

CURRENT EXTRAMURAL FUNDING

ATS/PHA, 1/2013-1/2014
PI: Todd M. Kolb, MD, PhD
"Regulation of right ventricular angiogenesis in hypoxic pulmonary hypertension by MIF"
The overall goals of this project are to: 1) provide definitive evidence that MIF is necessary for RV angiogenesis during ventricular remodeling in a murine model of chronic hypoxia-induced pulmonary hypertension with unbiased stereological methods; and 2) decipher the molecular mechanisms by which MIF regulates endostatin expression in cardiac myocytes. (Mentor: Paul M. Hassoun, MD).

NIH/NHLBI F32HL110516-01, 7/2011-7/2013
PI: Todd M. Kolb, MD, PhD
"Regulation of Hypoxic Pulmonary Hypertension by MIF"
The overall goal of this project is to determine whether MIF has a functional role in the regulation of right ventricular glucose metabolism and myocardial energy supply during chronic hypoxic pulmonary hypertension. I am the primary investigator on this mentored, post-doctoral individual fellowship award (Mentors: Paul M. Hassoun MD, Rachel L Damico, MD, PhD).

PREVIOUS EXTRAMURAL FUNDING

NIH/NIEHS F30 ES005925, 6/2000-6/2005
PI: Todd M. Kolb, MD, PhD
"Regulation of Apoptotic Signaling by Tsc2"
This pre-doctoral award supported my graduate and medical school training at the University of Maryland. The project focused on the regulation of kinase signaling pathways involved in renal epithelial cell apoptosis by the tumor suppressor protein Tsc2 (tuberous sclerosis complex-2) through its function as a GTPase activating protein (GAP) for the small GTPase Rap1. (Mentor: Myrtle A. Davis, DVM, PhD).

EDUCATIONAL ACTIVITIES

Educational Publications

Editorials:

  1. Kolb, TM, Damico, RL, and Hassoun, PM. 2011. Linking new and old concepts: Inflammation meets the Warburg phenomenon in pulmonary arterial hypertension. J Mol Med 89 (8): 729-32.

Case Reports:

  1. Larocca, CA, McEvoy, JW, Ellis, CL, Junkins-Hopkins, J, Kolb, T, Baer, AN, and Garibaldi, Brian T. 2012. Schnitzler’s syndrome associated with pancreatitis: a disease of IL-1 dysregulation. Clin Rheumatol 31(1): 169-74.
  2. Kolb, TM, Gilbert, C, Fishman, E, Terry, P, Pearse, D, Feller-Kopman, D, and Yarmus, L. 2012. Dieulafoy’s disease of the bronchus. Am J Resp Crit Care Med. In press.

Book Chapters:

  1. Kolb, TM. “Asthma,” in Patient Encounters: The Internal Medicine Work-Up, ed. B Garibaldi, S Bell, DC Files, and P Troy, 163-171. Philadelphia: Lippincott Williams and Wilkins. 2009.
  2. Kolb, TM and Hassoun, PM. “Treatment of pulmonary hypertension,” in Scleroderma: From Pathogenesis to Comprehensive Management, ed. J Varga, CP Denton, and FM Wigley. New York: Springer. 2012.

CME Publications:

  1. Kolb, TM and Hassoun, PM. 2011. Interactive learning module: SSc case with severe and progressive ILD and PH associated ILD. EULAR On-line course in SSc. www.eular.org.
  2. Kolb, TM. 2011. Efficacy and Safety of Controller Medications in Asthma. Respiratory Report 6(1). www.respiratoryreport.com.

Teaching

Classroom instruction:
2010-present: Johns Hopkins School of Medicine, Year One Journal Club, Clinical Discussant.

Clinical instruction:
July 2012-present: Johns Hopkins Hospital, Carol Johns Service Curriculum, Pleural Disease, Syllabus design and lecturer.

CLINICAL ACTIVITIES

Certification

  • Maryland State Medical License, D68500
    2009-present
  • Diplomat, American Board of Internal Medicine, #291817
    2008-present

ORGANIZATIONAL ACTIVITIES

Editorial Activities

  • 2011-present, Assistant Editor, ATS Pulmonary Circulation Assembly Online Journal Club
  • 2011-present, Reviewer, Practical Reviews in Critical Care Medicine, Oakstone Publishing
  • 2012-present, Reviewer, International Journal of Clinical Practice

Professional Societies

  • 2008-present, American Board of Internal Medicine
  • 2009-present, American Thoracic Society
  • 2008-present, Society of Critical Care Medicine
  • 2010-present, American College of Chest Physicians

RECOGNITION

  • 1997 UMBC Faculty Award for Excellence, Outstanding Undergraduate in Biology
  • 2000, Junior Investigator Travel Award; Society of Toxicology
  • 2000-2005, Ruth L. Kirschstein National Research Service Award, Individual Pre- Doctoral Fellowship; National Institute of Environmental Health Sciences
  • 2005, Alpha Omega Alpha; University of Maryland School of Medicine
  • 2005, University of Maryland School of Medicine Humanism Honor Society
  • 2008, The Gold Humanism Honor Society; University of Maryland School of Medicine
  • 2011-2013, Ruth L. Kirschstein National Research Service Award, Individual Post- Doctoral Fellowship; National
    Heart, Lung, & Blood Institute

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