Coordination Funds

协调基金

• 批准号: 515745040
• 负责人: Professor Dr. Björn Schumacher
• 金额: --
• 依托单位: Institute for Genome Stability in Ageing and Disease
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515745040?language=en
• 关键词: Coordination; Funds

The stability of the genome is constantly challenged by endogenous and exogenous genotoxic attacks. Cells combat these attacks by activating a DNA damage response (DDR) that promotes DNA repair and induces cell cycle arrest, apoptosis, and cellular senescence. While DNA repair mechanisms and the cellular DDR have been intensely investigated over the past decades, the physiological consequences of genome instability have only recently emerged. Indeed, it is now evident that DNA damage has complex consequences on the organism. In humans, DNA lesions not only cause cancer but also disturb homeostatic processes and consequently promote the aging process and the entire spectrum of age-related diseases, which is underlined by the fact that progeroid syndromes are caused by mutations in DNA repair genes. The Research Unit is comprised of a team of leading experts who propose a highly complementary and deeply interwoven research program aimed at gaining new insights into the physiological causes and consequences of genome instability. We will employ a range of experimental models with a particular emphasis on in vivo animal models, specifically the nematode C. elegans and mouse disease models. The Research Unit will investigate the poorly understood physiological roles of G-quadruplex structures and mechanical stress in challenging the integrity of the genome. We will explore the epigenetic and proteostatic regulatory mechanisms of homeostatic responses to DNA damage by investigating the specific and complex roles of histone remodeling and ubiquitin-mediated regulation of DNA damage signaling and repair. In addition, we will address how transcriptional stress, metabolic adaptation, altered epigenetic chromatin structure and nuclear stability as well as telomere dysfunction and activation of telomere maintenance mechanisms affect organismal homeostasis. We will do this both in the simple nematode worm and in murine progeroid, neurodegenerative and chronic kidney disease models. Taken together, the Research Unit ventures into the largely unexplored area of the physiological causes and consequences of genome instability and will thus significantly advance the current understanding of the impact of DNA damage and genotoxic stress on the organism. As such, the consortium paves the way for the future development of the field by generating synergy between an interdisciplinary group of scientists that explore the mechanistic underpinnings and also the clinical implications of homeostatic processes affected by genome instability.

基因组的稳定性不断受到内源性和外源性基因毒性攻击的挑战。细胞通过激活DNA损伤反应（DDR）来对抗这些攻击，所述DNA损伤反应促进DNA修复并诱导细胞周期停滞、凋亡和细胞衰老。虽然DNA修复机制和细胞DDR在过去几十年中得到了深入研究，但基因组不稳定性的生理后果最近才出现。事实上，现在很明显，DNA损伤对生物体具有复杂的后果。在人类中，DNA损伤不仅会导致癌症，而且还会扰乱体内平衡过程，从而促进衰老过程和整个年龄相关疾病谱，这一点通过DNA修复基因突变引起的早衰综合征这一事实得到强调。该研究单位由一个领先的专家团队组成，他们提出了一个高度互补和深入交织的研究计划，旨在获得对基因组不稳定性的生理原因和后果的新见解。我们将采用一系列实验模型，特别强调体内动物模型，特别是线虫C。线虫和小鼠疾病模型。研究单位将调查G-四链体结构和机械应力在挑战基因组完整性方面的鲜为人知的生理作用。我们将通过研究组蛋白重塑和泛素介导的DNA损伤信号传导和修复调控的特定和复杂的作用，探索DNA损伤的稳态反应的表观遗传和蛋白质稳定调控机制。此外，我们将讨论如何转录应激，代谢适应，改变表观遗传染色质结构和核稳定性以及端粒功能障碍和激活端粒维持机制影响生物体内平衡。我们将在简单的线虫和小鼠类早衰症、神经退行性疾病和慢性肾脏疾病模型中进行研究。总的来说，研究单位冒险进入基因组不稳定性的生理原因和后果的基本上未探索的领域，从而将显着推进目前对DNA损伤和遗传毒性压力对生物体的影响的理解。因此，该联盟通过在一个跨学科的科学家小组之间产生协同作用，为该领域的未来发展铺平了道路，该科学家小组探索了受基因组不稳定性影响的稳态过程的机制基础和临床意义。