Molecular mechanism of organ remodeling : Gene transcription and cell-cell interaction in mesenchymal

器官重塑的分子机制:间充质中的基因转录和细胞间相互作用

基本信息

  • 批准号:
    14104012
  • 负责人:
  • 金额:
    $ 68.89万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
  • 财政年份:
    2002
  • 资助国家:
    日本
  • 起止时间:
    2002 至 2006
  • 项目状态:
    已结题

项目摘要

External stress activates local cells of the mesenchymal origin (e.g., fibroblasts and smooth muscle cells) and inflammatory cells. Interactions between these cells promote fibrosis, organ hypertrophy, and structural remodeling. These changes affect the function of organs and result in organ failure including heart failure, renal failure, and liver failure. Thus, elucidation of molecular mechanisms underlying the tissue remodeling would lead to development novel therapeutic strategies for protection of normal organ function. We identified a Kruppel-like zinc finger transcription factor BTEB2 that is important for atherosclerosis, restenosis after angioplasty, tissue fibrosis, and cardiac hypertrophy. We also found that the ageing related factor Klotho inhibits tissue remodeling of the cardiovascular system. In this research project, we have analyzed transcriptional regulation and signal transduction that control tissue remodeling. The goals of the project were : 1)elucidation of the transcription factor network involved in activation of mesenchymal cells in tissue remodeling ; 2)elucidation of signal transduction mechanisms involved in the protective function of the Klotho factor against stress in the cardiovascular system ; and 3)development of drugs targeting transcription factors and humoral factors that are important for remodeling. We demonstrated that KLF5 plays essential roles in stress responses in both cardiovascular and metabolic systems. KLF5 interacts with transcription factors, such as PPARγ and RARα, cofactors, such as p300, and apoptosis-related genes, such as PARP to control stress response and to mediate tissue remodeling. To develop novel therapeutics targeting the KLF5 molecular network, we found a synthetic retinoid Am80 disrupts the interaction between KLF5 and RARα and inhibits KLF5's function. We showed that Am80 inhibited neointima formation and atherogenesis. We also demonstrate that klotho exhibits vascular protective effects.
外部应激激活间质来源的局部细胞(如成纤维细胞和平滑肌细胞)和炎性细胞。这些细胞之间的相互作用促进纤维化、器官肥大和结构重塑。这些变化影响器官的功能,导致器官衰竭,包括心力衰竭、肾功能衰竭和肝功能衰竭。因此,阐明组织重塑的分子机制将有助于开发新的治疗策略来保护正常的器官功能。我们鉴定了一种Kruppel样的锌指转录因子BTEB2,它在动脉粥样硬化、血管成形术后再狭窄、组织纤维化和心肌肥厚中起重要作用。我们还发现,衰老相关因子Klotho抑制心血管系统的组织重塑。在这个研究项目中,我们分析了控制组织重塑的转录调控和信号转导。该项目的目标是:1)阐明参与组织重塑中间充质细胞激活的转录因子网络;2)阐明Klotho因子在心血管系统中针对应激保护作用的信号转导机制;3)开发针对转录因子和体液因子的药物,这些转录因子和体液因子对组织重塑具有重要作用。我们证明了KLF5在心血管和代谢系统的应激反应中扮演着重要的角色。KLF5与PPARγ和RARα等转录因子、P300等辅因子和PARP等凋亡相关基因相互作用,控制应激反应,介导组织重塑。为了开发针对KLF5分子网络的新的治疗药物,我们发现合成的维甲酸AM80可以破坏KLF5与RARα之间的相互作用,并抑制KLF5的S功能。我们发现AM80抑制新生内膜的形成和动脉粥样硬化的形成。我们还证明了Klotho具有血管保护作用。

项目成果

期刊论文数量(36)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Kruppel-like transcription factor KLFS is a key regulator of adipocyte differentiation
Kruppel 样转录因子 KLFS 是脂肪细胞分化的关键调节因子
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Oishi Y
  • 通讯作者:
    Oishi Y
Yamauchi, T.: "Cloning of adiponectin receptors that mediate antidiabetic metabolic effects."Nature. 423・6941. 762-769 (2003)
Yamauchi, T.:“介导抗糖尿病代谢作用的脂联素受体的克隆。”《自然》423·6941(2003)。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Sakamoto, H.: "Smooth muscle cell outgrowth from coronary atherectomy specimens in vitro is associated with less time to restenosis and expression of a key Transcription factor KLF5/BTEB2."Cardiology. 100・2. 80-85 (2003)
Sakamoto, H.:“体外冠状动脉粥样斑块切除标本中的平滑肌细胞生长与再狭窄时间缩短和关键转录因子 KLF5/BTEB2 的表达有关。”心脏病学 100・2。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Functional interaction between the transcription factor Kruppel-like factor 5 and poly(ADP-ribose) polymerase-1 in cardiovascular apoptosis
  • DOI:
    10.1074/jbc.m608098200
  • 发表时间:
    2007-03-30
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Suzuki, Toru;Nishi, Toshiya;Nagai, Ryozo
  • 通讯作者:
    Nagai, Ryozo
Sata M.: "Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis"Nature Medicine. 8・4. 403-409 (2002)
Sata M.:“造血干细胞分化为参与动脉粥样硬化发病机制的血管细胞”,《自然·医学》8·403-409(2002)。
  • DOI:
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  • 期刊:
  • 影响因子:
    0
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NAGAI Ryozo其他文献

NAGAI Ryozo的其他文献

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{{ truncateString('NAGAI Ryozo', 18)}}的其他基金

KLF network in chronic diseases and cancer
KLF 慢性病和癌症网络
  • 批准号:
    22229006
  • 财政年份:
    2010
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
Molecular mechanisms that control stress response and tissue remodeling by cardiometabolic and immune systems
通过心脏代谢和免疫系统控制应激反应和组织重塑的分子机制
  • 批准号:
    19209029
  • 财政年份:
    2007
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
The systematic analysis on the diseases through the integration of the clinical data with the genomic information
通过临床数据与基因组信息的整合对疾病进行系统分析
  • 批准号:
    17019008
  • 财政年份:
    2005
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
Estimation of Susceptibility to and Prognosis of Cardiovascular Diseases Based on Genetic Polymorphism and Its Application to Drug Discoveries
基于遗传多态性的心血管疾病易感性和预后评估及其在药物研发中的应用
  • 批准号:
    12794012
  • 财政年份:
    2000
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for University and Society Collaboration
Development of inhibitors for the activation of cardiovascular interstitial ceils
心血管间质细胞激活抑制剂的开发
  • 批准号:
    11357007
  • 财政年份:
    1999
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Molecular mechanisms of vascular aging : analysis of a newly developed aging mouse
血管衰老的分子机制:对新开发的衰老小鼠的分析
  • 批准号:
    09044256
  • 财政年份:
    1997
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for international Scientific Research
Physiological function of ageing suppression gene klotho and its role in development of adult disease
衰老抑制基因klotho的生理功能及其在成人疾病发生发展中的作用
  • 批准号:
    09470159
  • 财政年份:
    1997
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular mechanisms of phenotypic modulation and growth of smooth muscle cells
平滑肌细胞表型调节和生长的分子机制
  • 批准号:
    09281102
  • 财政年份:
    1997
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas (A)
Development of therapeutic methods for arterial restenosis : intraarterial radiation, pharmaceutical approach and gene therapy
动脉再狭窄治疗方法的开发:动脉内放射、药物方法和基因治疗
  • 批准号:
    08557046
  • 财政年份:
    1996
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Pathogenesis and molecular mechanisms of arteral restenosis
动脉再狭窄的发病机制和分子机制
  • 批准号:
    06454287
  • 财政年份:
    1994
  • 资助金额:
    $ 68.89万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)

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转录因子芳基烃受体 (AHR) 介导的 CD96hi 细胞在 HIV 发病机制中的作用。
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