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Department of Molecular Pathogenesis

Members

Director Koichi Kokame
Laboratory chief Shigenori Honda, Masashi Akiyama, Yasuo Yamazaki, Hiroji Yanamoto
Staff scientist Yuka Eura-Higuchi
Postdoctoral fellow Keiko Yamato, Ayumi Yoshida, Yuichi Mishima, Yukako Nakajo, Hitomi Yamamoto-Imoto, Keiko Maruyama
Visiting researcher Kei Kamide, Fumiaki Banno
Researcher Chiaki Yokota, Akira Okamoto, Mana Mitsuguro
Trainee Toshiyuki Sakata
Research technician Hiroko Ikejima, Taiko Kunieda, Nozomi Momosaki
Administrative assistant Maki Yoshizuka

Research activities

The research programs of the Department of Molecular Pathogenesis address significant physiologic and pathophysiologic mechanisms that occur in the vascular system, brain, and kidney, including thrombotic and vascular diseases, hypertension, heart failure, hyperlipidemia, as well as the genetic base for these cardiovascular pathologies.

Laboratory of Thrombosis

The activity of the Laboratory of Thrombosis is aimed at understanding thrombus formation in health and diseases. We are actively engaged in the study of platelet thrombus formation under pathophysiological condition. One of our recent topics is the achievement of thrombosis thrombocytopenic purpura. We clarified the mechanism of this disease and developed the novel assay method for this disease. We revealed the prevalence of thrombosis-causing deficiency, such as protein C or protein S deficiency, in the Japanese general population. We also devote to the study of the endoplasmic reticulum stress in relation to the vascular diseases.

(A1) Millennium genome project: Genetic analysis for hypertension susceptible genes

  1. Okuda T, Fujioka Y, Kamide K, Kawano Y, Goto Y, Yoshimasa Y, Tomoike H, Iwai N, Hanai S, Miyata T : Verification of 525 coding SNPs in 179 hypertension candidate genes in the Japanese population: identification of 159 SNPs in 93 genes. J Hum Genet 47, 387-394, 2002.
  2. Kamide K, Tanaka C, Takiuchi, S, Miwa Y, Yoshii M, Horio T, Kawano Y, Miyata T : Six missense mutations of the epithelial sodium channel beta and gamma subunits in Japanese hypertensives. Hypertens Res 27, 333-338, 2004.
  3. Kamide K, Takiuchi S, Tanaka C, Miwa Y, Yoshii M, Horio T, Mannami T, Kokubo Y, Tomoike H, Kawano Y, Miyata T : Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes. Am J Hypertens 17, 446-449, 2004.
  4. Tanaka C, Kamide K, Takiuchi S, Kawano Y, Miyata T : An alternative fast and convenient genotyping method for the screening of angiotensin converting enzyme gene polymorphisms. Hypertens Res 27, 367-371, 2004.
  5. Okuda T, Sumiya T, Iwai N, Miyata T : Difference of gene expression profiles in spontaneous hypertensive rats and Wistar-Kyoto rats from two sources. Biochem Biophys Res Commun 313, 647-653, 2004.

(A2) Mechanisms of the platelet-thrombus formation

  1. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, Tamai H, Konno M, Kamide K, Kawano Y, Miyata T, Fujimura Y : Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 99: 11902-11907, 2002.
  2. Soejima K, Matsumoto M, Kokame K, Yagi H, Ishizashi H, Maeda H, Nozaki C, Miyata T, Fujimura Y, T Nakagaki : ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood 102: 3232-3237, 2003.
  3. Kokame K, Matsumoto M, Fujimura Y, Miyata T : VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood 103: 607-612, 2004.
  4. Matsumoto M, Kokame K, Soejima K, Miura M, Hayashi S, Fujii Y, Iwai A, Ito E, Tsuji Y, Takeda-Shitaka M, Iwadate M, Umeyama H, Yagi H, Ishizashi H, Banno F, Nakagaki T, Miyata T, Fujimura Y : Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood 103: 1305-1310, 2004.
  5. Banno F, Kaminaka K, Soejima K, Kokame K, Miyata T : Identification of strain-specific variants of mouse Adamts13 gene encoding von Willebrand factor-cleaving protease. J Biol Chem 279: 30896-30903, 2004.

(A3) Genetic bases on thrombosis in Japanese

  1. Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, Tamai H, Konno M, Kamide K, Kawano Y, Miyata T, Fujimura Y : Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A 99, 11902-11907, 2002.
  2. Okamoto A, Sakata T, Mannami T, Baba S, Katayama Y, Matsuo H, Yasaka M, Minematsu K, Tomoike H, Miyata T : Population-based distribution of plasminogen activity and estimated prevalence and relevance to thrombotic diseases of plasminogen deficiency in the Japanese: the Suita Study. J Thromb Haemost 1, 2397-2403, 2003.
  3. Sakata T, Okamoto A, Mannami T, Matsuo H, Miyata T : Protein C and antithrombin deficiency are important risk factors for deep vein thrombosis in Japanese. J Thromb Haemost 2, 528-530, 2004.
  4. Sakata T, Okamoto A, Mannami T, Tomoike H, Miyata T : Prevalence of protein S deficiency in the Japanese general population: the Suita Study. J Thromb Haemost 2, 1012-1013, 2004.

(A4) Mechanisms of the cellular response to the endoplasmic reticulum stress

  1. Kokame K, Kato H, Miyata T : Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis: GRP78/BiP and novel genes. J Biol Chem 271 : 29659-29665, 1996.
  2. Kokame K, Agarwala KL, Kato H, Miyata T : Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. J Biol Chem 275 : 32846-32853, 2000.
  3. Kokame K, Kato H, Miyata T : Identification of ERSE-II, a new cis-acting element responsible for the ATF6-dependent mammalian unfolded protein response. J Biol Chem 276 : 9199-9205, 2001.
  4. Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T : Characterization of the human NDRG gene family: A newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73 : 86-97, 2001.
  5. Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, Miyata T : Ndrg1-deficient mice exhibit progressive demyelinating disorder of peripheral nerves. Mol Cell Biol 24 : 3949-3956, 2004.

Laboratory of Cerebrovascular disorders (Surgical section)

(B1) Induction of infarct tolerance and activation of endogenous neurogenesis

To develop a new neuroprotective intervention, or neuro-regenerative treatment against cerebral damage following ischemic stroke, we are studying the mechanism of infarct tolerance development, or the endogenous neurogenesis activation. We are also studying the neuroprotective, or neuronal differentiation-promoting role of brain-derived neurotrophic factor.

References
  1. Yanamoto H, Xue J-H, Miyamoto S, Nagata I, Nakano Y, Murao K, Kikuchi H: Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanism. Brain Res 1019: 178-188, 2004.
  2. Yanamoto H, Tohnai N, Nishimori K, Xue J-H, Sakata N, Kikuchi H, Nagata I: Cortical spreading depression can evoke extensive neurogenesis in adult rat brain. J. Cereb Blood Flow Metab 23, S539, 2003
  3. Yanamoto H, Mizuta I, Nagata I, Xue J-H, Zhang Z, Kikuchi H: Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei. Brain Res 877: 331-344, 2000.

(B2) Development of animal stroke models to assess neuroprotective drugs, or to develop new interventions for ischemic stroke

Reliability of the stroke models in evaluating neuroprotective potentials is important for the development of neuroprotective drugs or interventions. We are developing animal models of cerebral infarction that can be utilized for various preclinical investigations.

References
  1. Yanamoto H, Nagata I, Niitsu Y, Xue JH, Zhang Z, Kikuchi H: Evaluation of MCAO stroke models in normotensive rats: Standardized neocortical infarction by the 3VO technique. Exp Neurol 182: 261-274, 2003
  2. Yanamoto H, Nagata I, Niitsu Y, Zhang Z, Xue J-H, Sakai N, Kikuchi H: Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia. Stroke 32: 232-239, 2001.
  3. Yanamoto H, Nagata I, Nakahara I, Tohnai N, Z Zhang, Tohnai N, Kikuchi H: Combination of intraischemic and postischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats. Stroke 30: 2720-2726, 1999.

(B3) Development of a new intervention for stenotic vascular lesions

By studying the mechanisms that contribute to the development of cerebral vasospasm or atherosclerotic vascular lesions, we are developing new interventions to prevent stenotic vascular lesion formation.

References
  1. Zhang Z, Nagata I, Kikuchi H, Xue J-H, Sakai N, Sakai H, Yanamoto H: Broad-spectrum, and selective serine protease inhibitors prevent expression of PDGF-BB and cerebral vasospasm after SAH: Vasospasm caused by cisternal injection of recombinant PDGF-BB. Stroke 32: 1665-72, 2001.
  2. Sawada M, Yanamoto H, Nagata I, Hashimoto N, Nakahara I, Akiyama Y, Kikuchi H: Prevention of neointimal formation by a serine protease inhibitor, FUT-175 following carotid balloon injury in rats. Stroke 30: 644-650, 1999.
  3. Todaka T, Yokoyama C, Yanamoto H, Hashimoto N, Nagata I, Tsukahara T, Hara S, Hatae T, Morishita R, Aoki M, Ogihara T, Kaneda Y, Tanabe T: Gene transfer of prostacyclin synthase (PGIS) prevents initimal hyperplasia following carotid balloon injury in rats. Stroke 30: 281-479, 1999.
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