Novel ciliary regulation loops in Hedgehog-dependent tumor entities

Hedgehog（HH）信号传导在发育和肿瘤发生中实现了从细胞增殖到细胞分化的大量生物学效应。尽管这种信号系统在生理学和病理学中非常重要，但信号级联中的几个关键步骤仍然知之甚少。特别是鉴于未来的临床肿瘤治疗，新的HH调节电路的理解和可能的药物靶点的评价是非常重要的。在我们自己的初步工作中，我们能够鉴定HH通路中的新的阳性因子，这些因子在HH依赖性恶性肿瘤中过表达。这些作用是由这些蛋白质的配体驱动输入到初级纤毛中引起的，初级纤毛是对适当HH信号传导至关重要的细胞器。在拟议的项目中，我们的目标是表征这些新发现的纤毛信号分子的机制和功能水平。我们想了解哪些纤毛事件被这些蛋白激活，以及这些过程对HH诱导的髓母细胞瘤形成的影响。 为了解决这些问题，我们将应用一系列不同的体外方法，基因敲除动物以及小鼠肿瘤模型。

Hedgehog (HH) signaling implements a plethora of biological effects in development and tumorigenesis ranging from cell proliferation to cell differentiation. Despite the great importance of this signaling system in physiology and pathology, several key steps in the signaling cascade are still only poorly understood. Particularly in light of a future clinical tumor therapy, the understanding of novel HH regulatory circuits and the evaluation of possible drug targets is of high significance. In our own preliminary work, we were able to identify novel positive factors in the HH pathway, which are overexpressed in HH-dependent malignancies. These effects are evoked by the ligand-driven import of these proteins into the primary cilium, a cellular organelle crucial for proper HH signaling. In the proposed project, we aim to characterize these newly identified ciliary signaling molecules on a mechanistic and functional level. We would like to understand which ciliary events are activated by these proteins and which impact these processes have on HH-induced medulloblastoma formation. To address these issues, we will apply a diverse set of in vitro approaches, genetic knock-out animals as well as murine tumor models.