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

重组粒细胞集落刺激因子（rG-CSF）缓解心脏、脑和四肢缺血的功能后果。rg - csf介导的骨髓源性细胞的动员，导致它们在缺血组织中增加归巢，在那里它们可以通过旁分泌机制起作用，可能是这种作用的基础。此外，rG-CSF可能在缺血组织中发挥直接作用，因为其受体（G-CSFR）在包括血管细胞在内的各种常驻细胞类型上表达。然而，尽管rG-CSF的治疗效果是无可争议的，但内源性G-CSF在缺血性疾病自主再生中的作用仍是谜。因此，本项目将利用G-CSF和G-CSFR敲除小鼠在小鼠后肢缺血模型中揭示内源性G-CSF对代偿性血管生长的影响。为了研究G-SCF信号缺陷对这些小鼠的功能影响，将应用激光多普勒灌注成像（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，但尚未明确探讨rG-CSF的作用（见上文）。因此，我们将利用几种转基因骨髓嵌合小鼠来揭示内源性G-CSF和外源性rGCSF的可能作用机制。这些研究将包括分析骨髓细胞依赖性和非依赖性G-CSF在代偿性血管生长中的相对贡献。细胞活动，如增殖，分化和凋亡可能有助于这些影响应进行调查。

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.