Mechanisms and meaning of activation of Hypoxia-Inducible-Factor-1 (HIF-1) in muscle after mechanical trauma

低氧诱导因子-1(HIF-1)是确保低氧组织充分适应缺氧的关键转录因子。HIF-1调控的基因包括铁和能量代谢、血管舒张性、血管发育和重塑以及血液的含氧量。除缺氧外，受损组织释放的介质，即反应性O2-和N2-物种以及细胞因子，都可以激活HIF-1。在动物模型和细胞培养研究中，将研究缺氧/复氧以及上述非缺氧刺激对HIF-1激活的程度和机制。通过体内双光子和单光子多聚焦激光显微镜，可以监测创伤后组织对HIF-1靶基因的反应，并通过局部结构性激活的HIF-1过表达来进行修饰。在具有组织特异性HIF-1基因敲除的小鼠中，将研究缺乏HIF-1的后果。在与SPP1151的其他合作伙伴的密切合作下，我们的研究将包括创伤的潜在介体以及患者的组织标本。我们关于HIF-1在机械性肌肉创伤中的作用的研究结果可能为严重创伤后组织修复的新的治疗理念提供基础。

Hypoxia inducible factor 1 (HIF-1) is the key regulatory transcription factor that ensures adequate adaptation of hypoxic tissue to the shortage of oxygen. HIF-1 regulated genes cover iron and energy metabolism, vasomotor tone, vascular development and remodeling and oxygen capacity of the blood. In addition to hypoxia, mediators released from damaged tissue, i.e. reactive O2- and N2-species and cytokines, can activate HIF-1. In an animal model as well as cell culture studies the extent and the mechanisms of HIF-1 activation by hypoxia/reoxygenation as well as the above mentioned non-hypoxic stimuli will be investigated. By in vivo 2-photon and 1-photon multifocal laser microscopy the tissue response after trauma with respect to HIF-1 target genes will be monitored and modified by local constitutively active HIF-1 overexpression. In mice with a tissue specific HIF-1 knock-out consequences of the lack of HIF-1 will be studied. In close cooperation with other partners of the SPP 1151 specifically potential mediators of trauma as well as tissue specimen from patients will be included in our study. Our findings on the role of HIF-1 in mechanical muscle trauma could provide the basis for new therapeutic concepts of tissue repair after severe trauma.