Graduate School of Medicine „Human Science
„ Molecular Medicine and therapeutics

Professor: Takayuki SHINDO
Associate Professor: Takayuki SAKURAI
Assistant Professor: Akiko KAMIYOSHI

Summary of Activity
We are studying the mechanisms of diseases such as atherosclerosis, hypertension, and organ dysfunctions, and developing new therapies. We have succeeded in generating original genetically-engineered animal models and are working vigorously on molecular medicine and therapeutics using these models. Our laboratory is the newest at Shinshu University but we are the only laboratory that can handle the entire course of planning, generating, and analysis of original gene-engineered mice. Experience with us the excitement of new discoveries that may very well become novel therapies for diseases.


Research Projects
To develop new therapies, we must employ various techniques that are available to todayfs medical science (not only animal experiments, but also gene-engineering, biochemistry, physiology, and pathology). Our students learn various important techniques used in medical science, as well as how to manipulate ES-cells and embryos.

Research themes of our laboratory are as follows;
1. Developing novel therapy by using models of atherosclerosis, hypertension, heart failure, renal failure, and liver dysfunction.
2. Pathophysiological analysis of vasoactive peptides and their receptors
3. Therapeutic angiogenesis
4. Developing novel techniques in gene-engineering and embryo-manipulation. Generation and analysis of new models.

For example, I want to describe adrenomedullin (AM)-knockout mice, which we generated. AM was originally identified as a vasodilating peptide. By generating AM-knockout mice, we first found that they are embryonic lethal with severe hemorrhage and edema (See figures). This is because the vascular structure of AM-knock out mouse embryos is fragile. We found that AM is a novel angiogenic factor, which is necessary for vascular stability. Studies using AM are currently underway for the new technique of therapeutic angiogenesis.

References
  1. Iinuma N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Arai T, Yoshizawa T, Koyama T, Uetake R, Kawate H, Muto S, Tagawa Y, Miyagawa S, Shindo T.: Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver. Peptides. 31 (5) 865-71. 2010

  2. Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y. Iinuma N, Kawate H, Yoshizawa T, Koyama T, Muto S, Shindo T.: EndogenousƒΏ-calcitonin gene-related peptide mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A. Liver International. 29 (5) 642-9. 2009

  3. Ichikawa-Shindo Y, Sakurai T, Kamiyoshi A, Kawate H, Iinuma N, Yoshizawa T, Koyama T, Fukuchi J, Iimuro S, Moriyama N, Kawakami H, Murata T, Kangawa K, Nagai R, Shindo T. GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity.J Clin Invest. 118(1):29-39. 2008

  4. Kusano S, Kukimoto-Niino M, Akasaka R, Toyama M, Terada T, Shirouzu M, Shindo T, Yokoyama S. Crystal structure of the human receptor activity-modifying protein 1 extracellular domain. Protein Sci. 17(11):1907-14. 2008

  5. Sakurai T, Kamiyoshi A, Watanabe S, Sato M, Shindo T. Rapid zygosity determination in mice by SYBR Green real-time genomic PCR of a crude DNA solution. Transgenic Res. 17(1):149-55. 2008

  6. Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Fukuchi J, Kawate H, Muto S, Tagawa Y, Shindo T: Endogenous aCGRP protects against concanavalin A-induced hepatitis in mice. Biochem Biophys Res Commun. 343(1):152-8. 2006

  7. Iimuro S, Shindo T et al.; Angiogenic effects of adrenomedullin in ischemia and tumor growth. Circ Res 95:415-423, 2004

  8. Niu P, Shindo T et al.; Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis and renal damage. Circulation 109:1789-1794, 2004