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Integrative nuclear modulation of the Hedgehog transcriptional profile (.2)

Hedgehog 转录谱的整合核调节 (.2)

基本信息

批准号：
329203264
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：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/329203264?language=en
关键词：
Integrative nuclear modulation Hedgehog transcriptional

项目摘要

Responding to changing environmental conditions and implementing these changes into the cellular gene expression profile is highly important during many physiological processes. However, in the case of physical cues such as a changing substrate stiffness it is most often not entirely clear how such information is molecularly relayed to critical signaling nodes in order to impact on the cellular transcriptome. Here, we would like to focus on the Hedgehog (Hh)/GLI pathway, an essential signaling system in development and cancer. Our previous work hints to novel protein complexes (Actin-MAL-GLI1 and KDM-GLI1) capable of serving as molecular platforms gathering cellular information and conveying these data to the GLI1 transcription factor. Specifically, we will investigate how external cues such as substrate stiffness or cell-intrinsic information such as cell shape or metabolism impact on the Hh pathway and on Hh-driven physiological processes such as cell differentiation. This will be complemented by a detailed biochemical analysis of the two protein complexes previously identified by us. We believe that such integrative functions of protein complexes are of high significance for non-canonical pathway activation in physiological settings but also in pathological situations such as cancer or fibrosis. Hence, understanding the biology of these signaling complexes is crucial for future therapeutic interventions.

在许多生理过程中，响应变化的环境条件并将这些变化实施到细胞基因表达谱中是非常重要的。然而，在物理线索的情况下，例如改变基质硬度，通常不完全清楚这些信息如何在分子上传递到关键信号节点，以影响细胞转录组。在这里，我们将重点关注Hedgehog（Hh）/GLI通路，这是发育和癌症中的一个重要信号系统。我们以前的工作提示新的蛋白质复合物（肌动蛋白-MAL-GLI 1和KDM-GLI 1）能够作为分子平台收集细胞信息，并将这些数据传递给GLI 1转录因子。具体来说，我们将研究外部线索，如基板刚度或细胞的内在信息，如细胞形状或代谢的影响Hh通路和Hh驱动的生理过程，如细胞分化。这将通过对我们先前确定的两种蛋白质复合物的详细生化分析来补充。我们相信，蛋白质复合物的这种整合功能对于生理环境中的非经典途径激活以及病理情况如癌症或纤维化都具有重要意义。因此，了解这些信号复合物的生物学对于未来的治疗干预至关重要。