Coordination Funds

协调基金

• 批准号: 526185120
• 负责人: Professor Dr. Ian Frew
• 金额: --
• 依托单位: Zentrum für Translationale Zellforschung ZTZ
• 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/526185120?language=en
• 关键词: Coordination; Funds

There are more than 30,000 new cases of bladder cancer every year in Germany and there is a large unmet clinical need to develop better therapies for this disease. Unlike other types of epithelial cancers bladder urothelial carcinomas are characterized by very specific types of recurrent alterations in genes that encode epigenetic regulatory proteins, including loss of function mutations, chromosomal amplifications and aberrant overexpression. Moreover, these epigenetic mutations arise at the earliest stages of tumour formation, implicating dysregulation of chromatin accessibility, chromatin activation state and DNA methylation as important drivers of bladder cancers. Why these particular epigenetic alterations are so important in the bladder is unclear. The experimental focus of this Research Unit is to gain fundamental mechanistic insights into how epigenetic alterations affect the pathological processes that underlie bladder urothelial carcinoma formation and progression. We further aim to develop novel personalized, epigenetics-based therapies for individual bladder cancer patients to work towards improving clinical management of this disease. Our proposed Research Unit will establish a research program that combines the strengths of clinical urological oncology in Freiburg and Tübingen, with the molecular and histopathological resources in Aachen and the fundamental scientific epigenetics expertise of basic and translational research scientists in Freiburg and Aachen. This will provide a strong link between fundamental research, clinical research and patient management. Through close collaborations we will generate new urothelial carcinoma model systems based on genetically engineered cell lines, mouse bladder organoid cultures, autochthonous mouse cancer models, and the generation and analyses of a living biobank of molecularly- and genetically-characterized human bladder cancer organoid cultures. We will use these model systems in the context of our Pre-Clinical Translation Platform to explore the genetic and chemical vulnerabilities of epigenetic alterations in urothelial carcinoma. In parallel, we will undertake molecular and pathological analyses of large collections of archival pathology samples of human urothelial carcinomas at different stages of development. These studies will collectively provide new biological understanding of the underlying epigenetic networks of bladder cancer.

德国每年新增3万多例膀胱癌病例，有大量尚未得到满足的临床需求需要为这种疾病开发更好的治疗方法。与其他类型的上皮癌不同，膀胱尿路上皮癌的特征是编码表观遗传调节蛋白的基因出现非常特殊类型的反复变化，包括功能突变、染色体扩增和异常过度表达。此外，这些表观遗传突变出现在肿瘤形成的最早阶段，意味着染色质可及性、染色质激活状态和DNA甲基化的失调是膀胱癌的重要驱动因素。为什么这些特殊的表观遗传变化对膀胱如此重要，目前尚不清楚。这个研究单位的实验重点是获得关于表观遗传改变如何影响膀胱尿路上皮癌形成和发展的病理过程的基本机制的见解。我们的进一步目标是为个体膀胱癌患者开发新的个性化、基于表观遗传学的治疗方法，以努力改善这种疾病的临床管理。我们拟议的研究部将建立一个研究计划，将弗莱堡和图宾根的临床泌尿肿瘤学的优势与亚琛的分子和组织病理学资源以及弗莱堡和亚琛的基础和转译研究科学家的基础科学表观遗传学专业知识相结合。这将在基础研究、临床研究和患者管理之间提供强有力的联系。通过密切合作，我们将建立新的尿路上皮癌模型系统，其基础是基因工程细胞系、小鼠膀胱器官培养、原生小鼠癌症模型，以及具有分子和基因特征的人膀胱癌有机培养物活生物库的产生和分析。我们将在我们的临床前翻译平台的背景下使用这些模型系统来探索尿路上皮癌表观遗传改变的遗传和化学脆弱性。同时，我们将对人类尿路上皮癌不同发展阶段的大量档案病理样本进行分子和病理分析。这些研究将共同为膀胱癌潜在的表观遗传网络提供新的生物学理解。