The VHL/HIF-axis in the regulation of cellular stress resistance

Von Hippel-Lindau基因(VHL)的种系失活导致遗传性癌症综合征von Hippel-Lindau病，该综合征使患者易于在多个器官形成恶性肿瘤和良性肿瘤。此外，在所有散发性肾细胞癌中，超过80%的病例中发现VHL基因突变，使pVHL成为最显著的肾脏肿瘤抑制蛋白。作为E3泛素连接酶复合体的一部分，Von-Hippel-Lindau蛋白(PVHL)通过介导低氧诱导因子HIF-1α的蛋白酶体降解来调节细胞对低氧的反应。令人惊讶的是，我们和其他人最近可以证明，基因切割VHL-1，哺乳动物VHL基因的同源物秀丽线虫，可以诱导线虫长寿。线虫寿命的变化不仅是衰老研究中最好的模型系统之一。然而，更重要的是，它们反映出对一系列压力源的抵抗力增强。在pVHL的情况下，潜在的分子机制在很大程度上仍然难以捉摸。然而，现有的数据允许假设在有效的肿瘤抑制和对细胞损伤和再生的反应之间存在细胞平衡，这至少部分是通过激活缺氧诱导因子信号来调节的。在这个项目的框架内，我们将检验这一假设。这样，我们将阐明与MAP激酶信号通路的相互作用。此外，还将分析pVHL在调节应激抵抗中的细胞和组织特异性功能以及VHL/HIF轴的旁分泌非细胞自主效应。在过去，我们已经成功地使用线虫作为研究肾脏疾病发病机制的细胞机制的模型。因此，阐明该模式生物细胞应激抵抗的基本机制将有助于理解急性肾损伤背景下肾脏对应激的反应。有趣的是，一些临床试验现在正在评估延长线虫寿命的干预措施--如缺血预适应和热量限制--在手术或有机毒性药物治疗的背景下达到改善器官保护的潜力。阐明VHL-1依赖调节寿命和细胞抗应激能力的分子途径将是该项目的首要目标。线虫是研究其潜在分子机制和发现新的保护原理的完美模式生物。对这些机制的进一步了解将进一步加强pVHL、细胞应激抵抗、衰老和肿瘤发生之间的联系，并有助于寻找可能的新治疗靶点，例如在治疗和预防急性肾损伤方面。

Germline inactivation of the von Hippel-Lindau gene (VHL) causes the hereditary cancer syndrome von Hippel-Lindau disease, which predisposes affected individuals to the formation of malignant and benign tumors in several organs. In addition to this syndrome mutations in VHL are found in more than 80% of all cases of sporadic renal cell carcinoma making pVHL the most prominent renal tumor suppressor protein. As part of an E3 ubiquitin ligase complex, Von-Hippel-Lindau protein (pVHL) regulates the cellular response to hypoxia by mediating the proteasomal degradation of the hypoxia inducible factor HIF-1alpha. Surprisingly, we and others could recently demonstrate that genetic ablation of vhl-1, the Caenorhabditis elegans homolog of the mammalian VHL gene, induces longevity in the nematode. Changes in nematode lifespan are not only one of the best established model systems in aging research. Yet more importantly they reflect increased resistance to a row of stressors. In the case of pVHL the underlying molecular mechanisms have largely remained elusive. However the existing data allows to hypothesize the existence of a cellular balance between effective tumor suppression on the one hand and the response to cellular damage and regeneration on the other hand, which is regulated at least partly through activation of hypoxia-inducible factor signaling. In the framework of this project we are going to examine this hypothesis. Doing so we will clarify interaction with the MAP kinase signaling pathway. Furthermore both cell- and tissue-specific functions of pVHL in the regulation of stress resistance and paracrine non-cell autonomous effects of the VHL/HIF-axis will be analysed. We have already employed C. elegans as a model for studying cellular mechanisms of pathogenesis regarding renal disease successfully in the past. Accordingly clarifying the basic mechanisms of cellular stress resistance in this model organism will help understanding the renal response to stress in the context of acute kidney injury. Interestingly, several clinical trials are now evaluating the potential of interventions that increase C. elegans lifespan - such as ischemic pre-conditioning and caloric restriction - to reach improved organoprotection in the context of surgery or organotoxic pharmacological therapies. Shedding light on the molecular pathways involved in vhl-1 dependent regulation of lifespan and cellular stress resistance will be the overarching goal of this project. C. elegans is the perfect model organism to examine the underlying molecular mechanisms and to discover novel protective principles. Enhanced knowledge of these mechanisms will further strengthen the link between pVHL, cellular stress resistance, aging and tumorigenesis and contribute to the search for possible novel therapeutic targets e.g. in treatment and prevention of acute kidney injury.