PHA/ATS/Pfizer Research Fellowship in Pulmonary Arterial Hypertension Grant Winner 2011
Kazuyo Kegan, PhD
Anesthesiology and Critical Care Management
Johns Hopkins University School of Medicine
Title: "Hypoxia-inducible factor-1 mediates Th2 immune response during development of pulmonary hypertension"
Term: October 1, 2011 and will end September 30, 2013
Summary of Research Project:
Injury to endothelium may be a trigger of pulmonary vascular remodeling in pulmonary hypertension (PH). When the pulmonary endothelium becomes damaged, wound repair cascades are stimulated. Recently, bone marrow-derived cells and circulating immune cells have been suggested to be recruited to the site of remodeling vascular wall, as well as lung resident cells, for this repair process. Failure to stop the initial repair response could result in pathophysiological vascular remodeling. T lymphocytes that express CD4 are also known as T helper (Th) cells; they are regarded as the most prolific producers of cytokines. We have previously shown that Th2 cytokine IL-4 is critical to the initiation of proliferating activity in the pulmonary vasculature and development of PH. In this proposal, we will dissect the mechanism by which the Th2 response triggers endothelial injury and recruitment of bone marrow and immune cells to the site of remodeling vasculature during the development of PH. The purpose of this proposal is to provide a better guide for the therapies that are based on the central role of endothelial injury and circulating cell recruitment caused by innate immune response.
NAME: Kazuyo Kegan, PhD
POSITION TITLE: Research Associate
|INSTITUTION AND LOCATION
||FIELD OF STUDY
Kagoshima University Dept of Agriculture, Kagoshima, Japan
Kagoshima University School of Medicine, Laboratory and Vascular Medicine, Japan
Molecular Cell Biology and Hematology
|The United Graduate school of Agricultural Sciences, Kagoshima University, Kagoshima, Japan
||Molecular Cell Biology and Hematology
Positions and Honors
Positions and Employment:
- 1996-2004 Research Student/Research Assistant, Kagoshima University, Faculty of Medicine, Department of Laboratory and Molecular Medicine, Kagoshima, Japan
- 2004-2005 Research Trainee, Johns Hopkins Medical Institutions, Department of Anesthesiology and Critical Care Medicine, Baltimore, MD
- 2005-2006 Postdoctoral fellow, Johns Hopkins Medical Institutions, Department of Anesthesiology and Critical Care Medicine, Baltimore, MD
- 2006-present Research Associate, Johns Hopkins Medical Institutions, Department of Anesthesiology and Critical Care Medicine, Baltimore, MD
Other Experience and Professional Membership:
- 2007-present: American Heart Association
- 2007-present: Journal of Immunology, ad hoc reviewer
Honors and Awards
- 2003 Young Investigator Award, 1st Blood Vessel Orbis Meeting, Nagoya, Japan
- 2003 Thrombosis and Haemostasis article (#3, PMID: 12719786) was featured in the Thrombosis and Haemostasis's editorial topic and reviewed in that issue (Review article PMID: 12719771).
- 2006 Travel Award, Evolution of Pulmonary Hypertension: Emerging Diseases and Novel Therapeutics Meeting, Bethesda, MD
- 2009 The 11th Annual ACCM Research Day Silver Award (Pulmonary Division): The 11th Annual ACCM Research Day conference, Johns Hopkins University, Baltimore, MD
- 2010 The J Immunology article (#15, PMID: 20889544) was featured in the Journal of Immunology's editorial topic that highlights articles that are among the top 10% of articles published in the journal.
- 2010 The J Immunology article (#15, PMID: 20889544) was featured by the Faculty of 1000 Biology (F1000) and noted as one of the top 2% of all papers published.
Selected Peer-reviewed Publications
- Maruyama I, Nakata M, Yamaji K. Effect of leptin in platelet and endothelial cells; Obesity and arterial thrombosis. Annals of the New York Academy of Sciences 902:315-319 (2000). PMID: 10865855
- Yamaji K, Sarker KP, Maruyama I, Hizukuri S. Antioxidant effects of 1,5-Anhydro-D-fructose, a new natural sugar, in vitro. Planta Medica 68:16-19 (2002). PMID: 11842320
- Yamaji K, Sarker KP, Kawahara K, Iino S, Yamakuchi M, Hashiguchi T, Maruyama I.
Anandamide induces Apoptosis in Human Endothelial cells: Its regulation system and clinical implications. Thrombosis and Haemostasis 89:875-884 (2003). PMID: 12719786
- Biswas KK, Sarker KP, Abeyama K, Hashiguchi T, Yamakuchi M, Yamaji K, Kawahara K, Endo R, Kawahara K, Endo R, Suzuki K, Maruyama I. Membrane cholesterol but not putative receptors mediated Anandamide-induced Hepatocyte apoptosis. Hepatology 38 (5):1167-1177 (2003). PMID: 14578855
- Sarker KP, Biswas KK, Rosales JL, Yamaji K, Hashiguchi1 T, Lee KY, Maruyama I. Ebselen Inhibits NO-induced Apoptosis of Differentiated PC12 Cells via Inhibition of ASK1-p38 MAPK-p53 and JNK Signaling and Activation of p44/42 MAPK and Bcl-2. Journal of Neurochemistry 87 (6):1345-1353 (2003). PMID: 14713291
- Yamaji K, Sarker KP, Abeyama K, Maruyama I. Antiatherogenic effects of an Egg Yolk enriched garlic supplement. International Journal of Food Sciences and Nutrition 55(1): 61-66 (2004). PMID: 14630593
- Yamaji K, Wang Y, Liu Y, Abeyama K, Hashiguchi T, Uchimura T, Biswas KK, Iwamoto H, Maruyama I. Activated protein C, a natural anticoagulant protein, has antioxidant properties and inhibits lipid peroxidation and advanced glycation end products formation. Thrombosis Research 115(4):319-325 (2005). PMID: 15668192.
- Nakajima Y, Furuichi Y, Biswas KK, Hashiguchi T, Kawahara K, Yamaji K, Uchimura T, Izumi Y, Maruyama I. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-kappaB pathway inhibition. FEBS Lett. 23;580(2):613-619 (2006). PMID: 16406050
- Yamaji-Kegan K, Su Q, Angellini DJ, Champion HC, Johns RA. Hypoxia-induced mitogenic factor has pro-angiogenic and pro-inflammatory effects in the lung via VEGF and VEGF receptor-2. Am J Physiol Lung Cell Mol Physiol. 291(6): L1159-1168 (2006). PMID: 16891392
- Angelini DJ, Su Q, Yamaji-Kegan K, Fan C, Skinner JT, Champion HC, Crow MT, Johns RA. Hypoxia-Induced Mitogenic Factor (HIMF/FIZZ1/RELMá) Induces the Vascular and Hemodynamic Changes of Pulmonary Hypertension. Am J Physiol Lung Cell Mol Physiol. 296(4):L582-93 (2009). PMID: 19136574
- Angelini DJ, Su Q, Yamaji-Kegan K, Fan C, Teng X, Hassoun PM, Yang SC, Champion HC, Tuder RM, Johns RA. RELMâ is upregulated in the lungs of patients with scleroderma-associated pulmonary hypertension. Am. J. Respir. Cell. Mol. Biol., 41(5):553-561 (2009). PMID: 19251945
- Yamaji-Kegan K, Su Q, Angelini DJ, Johns RA. Interleukin-4 is pro-angiogenic in the lung under hypoxic conditions: Interleukin-4 in the hypoxia-induced pulmonary angiogenesis. J Immunology 182:5469-5476 (2009). PMID: 19380795
- Johns RA, Yamaji-Kegan K. Unveiling cell phenotypes in lung vascular remodeling. Am J Physiol Lung Cell Mol Physiol. 297: L1056-L1058 (2009). PMID: 19837847
- Angelini DJ, Su Q, Kolosova IA, Fan C, Skinner JT, Yamaji-Kegan K, Collector C, Sharkis SJ, Johns RA. Hypoxia-Induced Mitogenic Factor (HIMF/FIZZ1/RELMá) Recruits Bone Marrow-Derived Cells to the Murine Pulmonary Vasculature. PLoS One. 22;5(6):e11251 (2010). PMID: 20582166
- Yamaji-Kegan K, Su Q, Angelini DJ, Myers AC, Johns RA. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMá) increases lung inflammation and activate pulmonary microvascular endothelial cells via interleukin-4 dependent mechanism. J Immunology 185(9):5539-5548 (2010). PMID: 20889544
Ongoing Research Support
NIH NHLBI, Paul M. Hassoun, MD
"Molecular Determinants of Pulmonary Arterial Hypertension"
Project 4: Hypoxia-Induced Mitogenic Factor (FIZZ1) in Pulmonary Hypertension and Right Heart Failure
Principal Investigator: Roger A. Johns, MD, MHS
Aims: 1) Examine the role of HIMF/FIZZ1 in the mechanism of pulmonary hypertension using genomic and proteomic analysis in animal models 2) Use genomic, proteomic, and physiologic/pharmacologic approaches to examine HIMF effect on components of known downstream HIMF signaling pathways. 3) Identify the HIMF receptor(s) and/or binding partners in lung and heart utilizing proteomics to identify its interactome network and post-translational modifications. 4) Investigate the role and mechanism of HIMF inhibition in the protective and reversal actions of simvastatin and sildenafil on remodeling in of PAH.