The mission of Dr. Komatsu’s research is to take a multidisciplinary approach to address important unmet needs in various medical conditions associated with vascular disorders and abnormalities. The broad research background of the group allows them to bring multiple disciplines together to basic research, application, and technology development. The research focus of Dr. Komatsu’s laboratory is twofold. One is to investigate the molecular mechanisms of blood vessel formation, remodeling, and dysfunction. With this knowledge, they search for breakthrough solutions for the treatment of cancer, cardiovascular diseases, and vascular complications in various other conditions. The other research focus is to develop novel vascular targeting strategies for site-specific drug delivery to diseased organs and tissues.
The current research topics of the Komatsu Lab include the study of high endothelial venules in tertiary lymphoid structures (TLS) and their role in creating an immune landscape that is favorable for cancer immunotherapy. In a separate research program, the group investigates endothelial cell and pericyte signaling pathways responsible for the maturation and stability of blood vessels in an effort to find a way to restore normal function to pathologically regenerating or remodeling blood vessels. For the drug targeting focus area, Dr. Komatsu explores the use of specific peptides that selectively target drug delivery to the tumor vasculature, hypertensive pulmonary arteries, or inflamed endothelium in sepsis.
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.
Lab Website: Komatsu Laboratory, Johns Hopkins All Children's Hospital/All Children's Research Institute
Technology Expertise Keywords
Development of vascular targeting technology for organ/lesion-specific drug delivery; Development of vascular imaging technology
Sawada J, Perrot CY, Chen L, Fournier-Goss AE, Oyer J, Copik A, Komatsu M. High Endothelial Venules Accelerate Naive T Cell Recruitment by Tumor Necrosis Factor-Mediated R-Ras Upregulation. Am J Pathol. 2021; 191(2):396-414. PMID: 33159887
Perrot C, Herrera J, Fournier-Goss A, and Komatsu M. Prostaglandin E2 breaks down pericyte-endothelial cell interaction via EP1 and EP4-dependent downregulation of pericyte N-cadherin, connexin-43, and R-Ras. Scientific Reports. 2020; 10(1):11186. PMID: 32636414
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
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
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 |