We are conducting research to investigate molecular, genetical, and physiological mechanisms underlying development and postnatal regulation of vascular system. The vascular system plays critical roles not only in development and maintenance of our body by distributing nutrients and oxygen to cells, but also in variety of disease development. Pathology in vasculature itself causes atherosclerosis, obstructive vascular disorders, ischemic heart/brain diseases, etc. In addition, new formation of vasculature plays important roles in cancer growth, wound healing, diabetic retinopathy and so on.
Our current research interest is focused on the vascular responses to blood flow changes (hemodynamic changes). In response to long-term blood flow increase or decrease, blood vessels change their diameter and remodel themselves. Currently we are studying genes that are expressed during this remodeling process and their regulations.
Current projects are addressing the mechanisms by which vascular endothelium responses to flow shear stress. We have revealed that expression of an artery specific gene, actinic receptor-like kinase 1 (ALK1), is undetectable in most of the blood vessels in adult mice. Intriguingly, induced angiogenesis by wound healing or tumorigenesis prompted ALK1 expressions in nascent and feeding arteries. We showed that the ALK1 induction in feeding arteries is likely to be caused by increased shear stress.
ALK1 is a member of transforming growth factor beta (TGF-beta) type I receptors and the haploinsufficiency of this gene causes an autosomal dominant vascular disorder, known as hereditary hemorrhagic telangiectasia 2 (HHT2).
The first of two immediate projects is to analyze functions of ALK1 gene in vascular development and remodeling, using in vitro shear stress model as well as transgenic expression and conditional deletion of ALK1 in adult mice. The second project is to characterize induction mechanisms of ALK1, so that ALK1 regulatory fragment can be utilized for targeted gene expression in remodeling arteries. Transgenic mouse as well as viral transgene delivery techniques are used in this project.
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Seki T, Hong KH, Oh SP. 2006 Non-overlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab Invest 86:116-129.
Park S, Lee YJ, Lee HJ,
Seki T, Hong KH, Park J, Beppu H, Lim IK, Yoon JW, Kim SJ, Oh SP. 2004 B-cell translocation gene 2 (Btg2) regulates vertebral patterning by modulating BMP/Smad signaling. Mol Cell Biol 23:10256-62.
Seki T, Hong KH, Yun J, Kim SJ, Oh SP. 2004 Isolation of a regulatory region of activin receptor-like kinase 1 gene sufficient for arterial endothelium-specific expression. Circ Res 94:e72-7.
Seki T, Yun J, Oh SP. 2003 Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res 93:682-9.
Shi Y, Simmons MN,
Seki T, Oh SP, Sugrue SP. 2001 Change in gene expression subsequent to induction of Pnn/DRS/memA: increase in p21(cip1/waf1). Oncogene 20:4007-18.
Oh SP,
Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E. 2000 Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97:2626-31.
Saito K, Naito I,
Seki T, Oohashi T, Kimura E, Momota R, Kishiro Y, Sado Y, Yoshioka H, Ninomiya Y. 2000 Differential expression of mouse alpha5(IV) and alpha6(IV) collagen genes in epithelial basement membranes. J Biochem (Tokyo) 128:427-34.
Sado Y, Kagawa M, Naito I, Ueki Y,
Seki T, Momota R, Oohashi T, Ninomiya Y. 1998 Organization and expression of basement membrane collagen IV genes and their roles in human disorders. J Biochem (Tokyo) 123:767-76.
Seki T, Naito I, Oohashi T, Sado Y, Ninomiya Y. 1998 Differential expression of type IV collagen isoforms, alpha5(IV) and alpha6(IV) chains, in basement membranes surrounding smooth muscle cells. Histochem Cell Biol 110:359-66.
Ueki Y, Naito I, Oohashi T, Sugimoto M,
Seki T, Yoshioka H, Sado Y, Sato H, Sawai T, Sasaki F, Matsuoka M, Fukuda S, Ninomiya Y. 1998 Topoisomerase I and II consensus sequences in a 17-kb deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome. Am J Hum Genet 62:253-61.
