Novel ciliary regulation loops in Hedgehog-dependent tumor entities

Hedgehog依赖性肿瘤实体中的新型纤毛调节环

• 批准号: 247176801
• 负责人: Professor Dr. Matthias Lauth
• 金额: --
• 依托单位: Institut für Molekularbiologie und Tumorforschung (IMT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/247176801?language=en
• 关键词: Novel; ciliary; regulation; loops; Hedgehog

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.

Hedgehog （HH）信号传导在从细胞增殖到细胞分化的发育和肿瘤发生过程中实现了大量的生物学效应。尽管这一信号系统在生理学和病理学上具有重要意义，但人们对信号级联的几个关键步骤仍然知之甚少。特别是在未来的临床肿瘤治疗中，了解新的HH调控回路和评估可能的药物靶点具有重要意义。在我们自己的初步工作中，我们能够识别HH通路中新的阳性因子，这些因子在HH依赖性恶性肿瘤中过度表达。这些作用是由配体驱动的蛋白质输入初级纤毛引起的，初级纤毛是一种对HH信号传导至关重要的细胞器。在拟议的项目中，我们的目标是在机制和功能水平上表征这些新发现的纤毛信号分子。我们想了解哪些纤毛事件是由这些蛋白质激活的，以及这些过程对hh诱导的成神经管细胞瘤形成的影响。为了解决这些问题，我们将采用多种体外方法，基因敲除动物以及小鼠肿瘤模型。

项目成果

Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

• DOI: 10.1158/1535-7163.mct-14-0481
• 发表时间: 2015-03-01
• 期刊: MOLECULAR CANCER THERAPEUTICS
• 影响因子: 5.7
• 作者: Dhanyamraju, Pavan Kumar;Holz, Philipp Simon;Lauth, Matthias
• 通讯作者: Lauth, Matthias