| 研究課題/領域番号 |
25462812
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| 研究機関 | 筑波大学 |
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研究代表者 |
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| 研究期間 (年度) |
2013-04-01 – 2016-03-31
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| キーワード | 医学 / 外科系臨床医学 / 救急医学 / 集中治療学 / 敗血症 |
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| 研究実績の概要 |
We completed two years of current project. In Ist year, we mainly concentrated to explore the role of VEGF (Vascular endothelial growth factor) in the pathogenesis of lung injury and cardiac dysfunction in sepsis. In 2nd year, we made diabetic sepsis model and investigated VEGF expression in heart with other experiments. From our previous studies, we know that cardiac VEGF is downregulated in diabetic animals and this downregulation is aggravated when diabetic animals become septic. Endothelin blockade has potential role in reversing the downregulated VEGF cascade in heart tissues in diabetic septic animals. Again, we found that blockade of endothelin significantly normalizes the downregulation of VEGF in lung tissues in sepsis. In addition, protease activated receptor-2 and the blockade of TNF-alpha normalized the downregulated pulmonary VEGF expression in sepsis rat models. Treatment with landiolol, a selective ultra short acting beta blocker significantly reversed the decreased VEGF expression in heart tissues in sepsis with a potential impact on hemodynamics. This landiolol treatment has also significantly reversed the altered VEGF expression in sepsis liver tissues with mild morphological injuries. Thus, we state that aberrant expression of VEGF in sepsis organ complications are influenced by several factors including diabetes, endothelin system, protease activated receptors, beta adrenergic receptors and inflammatory cytokines.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The current research is on right track both from the contexts of time line and the amount of research activities scheduled to be done (100% done with target milestone achievement). In last two years, we understood a number of mechanisms responsible for the aberrant VEGF expression in various organ complications in sepsis. These mechanisms at least shed some light to the VEGF pathobiology in organ complication development in sepsis. In last two years, we used five types of pharmacological drug interventions in sepsis animals at various time points with various doses and systematically checking the effects of those drug treatments on VEGF expression in important sepsis-induced organ dysfunction (lung, heart, kidney, liver, brains). In addition, in 2nd year, we started to explore the role of diabetes in organ complications of sepsis in the context of VEGF pathobiology. We investigated in depth both protein and gene expression of target molecules to be assessed in the present study with respective organ function and morphology both in 1st and 2nd years of this project.
Systematically we studied the role of VEGF in organ complication in sepsis not only by using rat models but also other animal models like rabbit and mice, generating longer duration of sepsis models, using various techniques of sepsis induction, using animal models of both the compensatory and decompensatory phases of sepsis. We made more than 10 international publications from these research findings (four of them are in press now).
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| 今後の研究の推進方策 |
Since the start of this project, we have used several pharmacological approaches to reverse the organ specific VEGF expression alteration in sepsis of several duration and doses. In 1st year of this project, we mainly concentrated to the exploration of role of VEGF in pulmonary and cardiac dysfunction in septic models with various pharmacological interventions. In the 2nd year, we largely examined the effect of diabetes on aberrant VEGF expression in septic organ complications specially heart tissue. In 3rd year of this project, we will continue to study the effects of diabetes to the pathogenesis of sepsis organ complication. We also will concentrate to brain and kidney tissues investigation in context of VEGF pathobiology in sepsis models. We will dissect the molecular mechanisms through in vitro cell culture either primary or secondary. Various gene silencing technologies will be used. Human sample analysis: In collaboration of our another current project on sepsis (Kiban B by Professor Satoshi Gando) organ specimens (brain, heart, lung, liver, kidney) obtained at autopsy from individuals divided into two study groups (Sepsis group: Patients with a well-documented medical history and diagnosis of sepsis in vivo, according to the definition of the ACCP/SCCM Consensus Conference, all patients suffer the course of multiple organ failure due to sepsis; Control group: Autopsy cases with death due to various natural and unnatural causes, none of the individuals included in this study group should have a medical history of a septic condition prior to death).
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| 次年度使用額が生じた理由 |
This fiscal year we could not buy VEGF genetically manipulated animals for sepsis induction because of the large volumes of other animal research works of this project.
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| 次年度使用額の使用計画 |
Next fiscal year we will use that unused money from this year to generate VEGF genetically manipulated sepsis models.
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