2020 Notch Signaling in Development, Regeneration, and Diseases GRC/GRS

项目摘要 第五届戈登研究会议(GRC)关于Notch信号在发育、再生和疾病中的作用 (2020年7月19日至7月23日在缅因州贝茨学院)将解决美国科学研究中一个尚未得到满足的主要需求 通过召集学术界和工业界的科学家围绕一个根本重要的 与健康和疾病广泛相关的发育信号通路。虽然第一个“缺口表型” 是一个多世纪前描述的，研究阐明了导致Notch信号的分子事件 自20世纪80年代初克隆果蝇Notch受体基因以来，转导速度加快。 后来的研究表明，Notch信号需要细胞-细胞接触，建立了配体诱导的 Notch受体的蛋白分解产生一种转录调节因子，刺激靶基因的表达 基因，并证明翻译后修饰是调节配体受体的关键 互动。在模型生物中的研究证实了Notch信号在许多细胞命运中的重要性 决定。人类遗传学研究表明，核心Notch途径组件的突变是几个 发育综合征(如Alagille综合征、脊柱肋骨发育不良症、主动脉瓣疾病)和成人 起病(如CADASIL、各种心脏和瓣膜畸形)，同时导致或促成癌症 以组织依赖的方式启动或发展。除了在特定器官系统中的作用外，新的发现 还发现了Notch在免疫、炎症和代谢紊乱中的作用。缺口-目标 抗体和途径抑制剂已作为潜在的抗癌疗法进入临床试验，并正在 正在考虑其他适应症，但Notch调节器在临床上的有效部署仍在继续 在疗效方面提出了明显的挑战(肿瘤或疾病状态最有可能做出反应) 毒性，因为Notch在选定的成人组织(如肠道)的动态平衡中具有重要作用。 在过去成功的基础上，本次会议旨在提供一个充满活力的美国论坛，以刺激跨学科 在生物学这一重要领域的讨论和合作，培养了人们之间的共同体意识 研究人员，并欢迎新成员加入该领域。会议计划将汇聚来自 学术界、生物技术和制药业解决基本机制、发展、 使用尖端方法解决临床和治疗问题。被邀请的参与者包括 拥有丰富的机构记忆和许多具有令人兴奋的新技术的早期职业科学家的老牌“思想领袖” 调查结果。GRC会议的非正式和保密环境鼓励自由的科学交流 未发布的数据。纳入和整合专门面向博士后的戈登研究研讨会(GRS) GRC之前的研究生是吸引新科学家进入该领域的一项特殊资产，并鼓励 实习生参与。最重要的是，GRC/GRS组合格式在整合学生、博士后 以及希望进入一个新领域的研究人员，例如研究这一重要的信号通路。

Project Summary The fifth Gordon Research Conference (GRC) on Notch Signaling in Development, Regeneration & Disease (July 19 – July 23, 2020 at Bates College, Maine) will address a major unmet need in the American scientific community by convening scientists from both academia and industry around a fundamentally important developmental signaling pathway broadly relevant to health and disease. Although the first “Notch phenotype” was described over a century ago, studies elucidating the molecular events responsible for Notch signal transduction have accelerated since the early 1980s after cloning of the Drosophila Notch receptor gene. Subsequent studies showed that Notch signaling requires cell-cell contact, established that ligand-induced proteolysis of the Notch receptor produces a transcriptional regulator that stimulates expression of target genes, and demonstrated that post-translational modifications are critical to modulate ligand-receptor interactions. Studies in model organisms identified the importance of Notch signaling in numerous cell fate decisions. Human genetic studies showed that mutations of core Notch pathway components underlie several developmental syndromes (e.g. Alagille Syndrome, Spondylocostal Dysostosis, aortic valve disease) and adult onset diseases (e.g. CADASIL, various heart and valve malformations), while causing or contributing to cancer initiation or progression in a tissue-dependent manner. Beyond its role in specific organ systems, new findings have also uncovered a role for Notch in immune, inflammatory and metabolic disorders. Notch-targeted antibodies and pathway inhibitors have entered clinical trials as potential anti-cancer therapeutics and are being considered for other indications, but effective deployment of Notch modulators in the clinic continues to pose distinct challenges around efficacy (what tumors or disease states are most likely to respond), and toxicity, because of the importance of Notch in the homeostasis of selected adult tissues (such as the gut). Building on past success, this meeting aims to provide a vibrant US forum to stimulate cross disciplinary discussions and collaborations in this important area of biology, nurture a sense of community among researchers, and welcome new members into the field. The meeting program will bring together scientists from academia, biotech and the pharmaceutical industry addressing fundamental mechanistic, developmental, clinical and therapeutic questions using cutting-edge approaches. Invited participants include a blend of established “thought leaders” with vast institutional memory and many early career scientists with exciting new findings. The informal and confidential environment in GRC meetings encourages free scientific exchange of unpublished data. The inclusion and integration of a Gordon Research Seminar (GRS) exclusively for postdocs and graduate students prior to the GRC is a particular asset to draw new scientists into the field and encourage trainee participation. Most importantly, the combined GRC/GRS format excels in integrating students, postdocs and investigators wishing to enter a new field, such as the study of this important signaling pathway.