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Masanobu Komatsu, Ph.D.

Photo of Dr. Masanobu Komatsu, Ph.D.
  • Associate Professor of Orthopaedic Surgery

Research Interests

Normalization of pathologically remodeling/regenerating blood vessels

Background

Dr. Komatsu is a senior scientist in the Johns Hopkins All Children's Research Institute, Department of Surgery and the Cancer & Blood Disorders Institute. He is an Associate Professor in the Johns Hopkins University School of Medicine Department of Orthopaedic Surgery. He studies the malformation and malfunction of blood vessels and how these abnormalities impact medical conditions such as cancer, cardiovascular diseases, and neurological disorders. He hopes to discover ways to restore normal function to those vessels, which would have a profound effect on the efficacy of treatments.

Dr. Komatsu earned an undergraduate degree in marine science/biology and a Ph.D. in cell biology at the University of Miami, where he also did post-doctoral training in immunology. He continued post-doctoral studies at the Sanford Burnham Prebys Medical Discovery Institute under Dr. Erkki Ruoslahti who discovered fibronectin and integrins. In 2005, he became an Assistant Professor of the University of Alabama at Birmingham Department of Pathology, where he began investigating the molecular mechanism of blood vessel maturation. He joined Sanford Burnham as a faculty member in 2008 before coming to Johns Hopkins All Children’s in 2018 to continue his research at JHU. He holds patents related to the vascular regulation by R-RAS and peptide-mediated vascular targeting of pulmonary hypertension.

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Titles

  • Associate Professor of Orthopaedic Surgery

Departments / Divisions

Centers & Institutes

Education

Degrees

  • Ph.D., University of Miami Leonard M. Miller School of Medicine (Florida) (1998)
  • B.S., University of Miami (Florida) (1991)

Research & Publications

Research Summary

Malfunction and malformation of blood vessels are associated with a broad range of medical conditions, including cancer, cardiovascular diseases, and neurological disorders. The ultimate goal of Dr. Komatsu’s research is to find a way to reverse the process of abnormal vessel formation and remodeling, and restore normal function to these vessels. Normalization of blood vessels provides unique therapeutic opportunities. It can enhance the efficacy of cancer treatments, reestablish blood flow to ischemic hearts and limbs, avoid vascular complications in diabetes, and prevent blindness caused by damaging of the retina in diabetic and elderly people. Newly formed blood vessels must undergo a maturation process. The defects in this process result in the formation of functionally defective blood vessels, which is typically seen in pathological lesions. Dr. Komatsu’s research is uncovering key molecular pathways that promote the vessel maturation process.

Lab

Blood vessel formation and maturation are regulated by the balance between pro-angiogenic and antiangiogenic signals. Dr. Komatsu’s group has identified a key role for the small GTPase R-Ras in promoting vessel maturation while attenuating excessive angiogenic response in pathologically regenerating vasculature. R-Ras is highly expressed in fully differentiated, quiescent vascular smooth muscle cells, endothelial cells, and pericytes of the mature adult vasculature. Unlike prototypic oncoprotein Ras such as K-Ras, R-Ras inhibits vascular cell proliferation and invasion and promotes vascular quiescence. R-Ras signaling primarily affects vessel remodeling and regeneration by counterbalancing vessel activation. The elevated R-Ras expression normalizes pathologically regenerating vasculature.

Regulation of blood vessels by R-Ras

There is currently no successful strategy for promoting vascular maturation for therapeutic purposes. The studies conducted by Dr. Komatsu’s group showed that R-Ras coordinates multiple signaling events in endothelial cells and pericytes to redirect nascent vessel formation from angiogenic sprouting to vessel stabilization. The group also showed an important activity of R-Ras to facilitate tubulogenesis (creation of lumen) of growing vessels via non-canonical Akt pathway that stabilizes microtubule cytoskeleton. The unique multifaceted activities of R-Ras make the R-Ras pathways an important subject of the investigation to search for a new strategy for manipulating blood vessel function.

Innovation in drug delivery technology

The other area of Dr. Komatsu’s research is to develop novel vascular targeting strategies for delivery of therapeutics in various human diseases. Vascular targeting technology takes advantage of unique molecular signatures of blood vessels at specific sites in the body. This technology enables direct delivery of drugs to tumors and other diseased tissues through the vascular network. Since drugs are targeted to specific sites, it is possible to enhance the drug efficacy while substantially reducing unwanted side-effects of the drugs. 

Dr. Komatsu’s group succeeded in targeting the lung lesions of pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary vascular resistance. PAH is a serious lung disorder, which can lead to right heart failure and death. There is currently no effective treatment for PAH. Dr. Komatsu’s group used a 9 amino-acid cyclic peptide, CARSKNKDC (CAR) to selectively target PAH lesions. The unique property of the CAR peptide offers a novel drug delivery system for PAH.

Technology Expertise Keywords

Development of vascular targeting technology for organ/lesion-specific drug delivery; Development of vascular imaging technology

Selected Publications

Perrot C, Sawada J, and Komatsu M. Prolonged activation of cyclic AMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS. FASEB journal. 2018; 32(11): 5793-5812. PMID: 29775418

Li F, Sawada J, and Komatsu M. R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nature Communications. 2017; 8(1):1720, PMID: 29170374

Sawada J, Urakami T, Li F, Urakami A, Zhu W, Fukuda M, Li DY, Ruoslahti E, Komatsu M. Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels. Cancer Cell. 2012 Aug 14;22(2):235-49. doi: 10.1016/j.ccr.2012.06.013. PMID: 22897853

Urakami T, Järvinen TA, Toba M, Sawada J, Ambalavanan N, Mann D, McMurtry I, Oka M, Ruoslahti E, Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension. Am J Pathol. 2011 Jun;178(6):2489-95. doi: 10.1016/j.ajpath.2011.02.032. PMID: 21549345

Komatsu M, Ruoslahti E. R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis. Nature Medicine 2005 Dec;11(12):1346-50. PMID: 16286923

Patents

R-Ras activity in vascular regulation
Patent # U.S. Patent No. US8506965 B2

CAR Peptide for Homing, Diagnosis & Targeted Therapy for Pulmonary and Fibrotic Disorders
Patent # U.S. Patent No. US9180161 B2

Contact for Research Inquiries

600, 5th street South
St. Petersburg, FL 33701 map

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Activities & Honors

Memberships

  • American Association for Cancer Research
  • American Heart Association
  • North American Vascular Biology Organization
  • American Thoracic Society

Videos & Media

Recent News Articles and Media Coverage

Study sheds light on how the body forms new blood vessels, Futurism, Nov 2017

Top stories of 2017: #10) Scientists find key to regenerating blood vessels, EurekAlert!, Dec 2017

Angiogenesis - Latest research and news, Ivanhoe Broadcast, Feb 2018

Getting the ‘Akt’ straight in angiogenesis, DDNews, Mar 2018

Molecule that fixes “leaky” blood vessels can impact cancer, stroke, and blindness, SBP Beaker Blog, (March 2015)

To treat breast cancer, give it a lifeline, SBP Beaker Blog, (October 2016)

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