Cellular mechanisms of regenerative effects of granulocyte colony-stimulating factor (G-CSF) in hindlimb ischemia

粒细胞集落刺激因子（G-CSF）在后肢缺血中再生作用的细胞机制

• 批准号: 35286742
• 负责人: Professorin Dr. Sigrid Nikol
• 金额: --
• 依托单位: Max-Planck-Institut für Herz- und Lungenforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/35286742?language=en
• 关键词: Cellular; mechanisms; regenerative; effects; granulocyte

Recombinant granulocyte colony-stimulating factor (rG-CSF) relieves the functional consequencesof ischemia in heart, brain and limbs. rG-CSF-mediated mobilization of bone marrow-derived cells,leading to their increased homing in the ischemic tissue where they could act by paracrinemechanisms, may underly this effect. In addition or alternatively, rG-CSF may exert direct effects inthe ischemic tissue as its receptor (G-CSFR) is expressed on various resident cell types including vascular cells. However, while therapeutic effects of rG-CSF are indisputable the role of endogeneous G-CSF in autonomous regeneration in ischemic diseases is enigmatic. Therefore, the present project shall reveal the impact of endogeneous G-CSF for compensatory vessel growth in a murine hindlimb ischemia model using G-CSF- and G-CSFR knockout mice. To examine the functional consequences of deficient G-SCF signalling in these mice Laser Doppier Perfusion Imaging (LDPI) and Nuclear Magnetic Resonance Imaging (NMRI) will be applied. The mechanisms of potential effects of endogeneous G-CSF may be those currently discussed, but not definitively explored for rG-CSF effects (see above). Therefore, several types of transgenic, bone marrow-chimeric mice will be used to reveal possible mechanisms of action of endogeneous G-CSF and exogeneous rGCSF in parallel. These investigations will comprise the analysis of the relative contributions of bone marrow cell-dependent and -independent G-CSF effects in compensatory vessel growth. Cellular activities, such as proliferation, differentiation and apoptosis potentially contributing to these effects shall be investigated.

重组粒细胞集落刺激因子(rg-CSF)可减轻心、脑和四肢缺血的功能后果。RG-CSF介导的骨髓来源细胞的动员，导致它们在缺血组织中的归巢增加，在那里它们可以通过旁机制发挥作用，这可能低于这一效应。此外，rg-CSF可能通过其受体(G-CSFR)在包括血管细胞在内的各种驻留细胞上表达，从而在缺血组织中发挥直接作用。然而，尽管重组人粒细胞集落刺激因子的治疗效果是毋庸置疑的，但内源性粒细胞集落刺激因子在缺血性疾病自主再生中的作用仍是个谜。因此，本项目将利用G-CSF和G-CSFR基因敲除小鼠，揭示内源性G-CSF对小鼠后肢缺血模型中代偿性血管生长的影响。为了检查这些小鼠G-SCF信号缺陷的功能后果，将应用激光多普勒血流成像(LDPI)和核磁共振成像(NMRI)。内源性G-CSF的潜在作用机制可能是目前讨论的，但对于rg-CSF的作用还没有明确的探索(见上文)。因此，几种类型的转基因骨髓嵌合小鼠将被用来揭示内源性G-CSF和外源性rGCSF平行发挥作用的可能机制。这些研究将包括对骨髓细胞依赖和非独立G-CSF效应在代偿性血管生长中的相对贡献的分析。应调查可能导致这些效应的细胞活动，如增殖、分化和凋亡。