Project Summary The fourth Notch Signaling in Development, Regeneration & Disease meeting (July 22 ? July 27th, 2018 at Bates College, Maine) addresses 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 components and molecular events responsible for Notch signal transduction have accelerated since the early 1980s following the cloning of the Drosophila Notch receptor. Such studies have shown that Notch signal transduction requires cell-cell contact, have established that ligand- induced proteolysis of Notch produces a transcriptional regulator that stimulates expression of target genes, and have demonstrated that post-translational modifications of the receptor are critical for modulating ligand- responsiveness. Studies in model organisms have demonstrated the importance of the Notch pathway in numerous cell fate decisions, and human genetic studies have now established that mutations of core Notch pathway components underlie several developmental syndromes (Alagille's Syndrome, Spondylocostal Dysostosis, aortic valve disease), adult onset diseases (CADASIL, various heart and valve malformations) and cause or contribute to cancer initiation, promotion or progression in a tissue-dependent manner. Antibodies and pathway inhibitors directed at Notch dependence in certain cancers with gain-of-function mutations have entered clinical trials for testing as potential anti-cancer therapeutics, but effective deployment of Notch modulators in the clinic poses distinct challenges around efficacy (what tumors are most likely to respond), and around toxicity because of the importance of Notch in maintaining homeostasis of certain adult tissues (such as the gut). Thus, the main goal of the meeting is to establish a US forum to stimulate cross-disciplinary discussions and collaborations among participating scientists in this critically important area of developmental biology and signaling, and nurture a developing sense of community among researchers in 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 diverse approaches. The invited participants include a blend of established ?thought? leaders with vast institutional memory and early career scientists with exciting new findings. Importantly, the informal and confidential environment of Gordon conferences (GRCs) encourages free scientific exchange. Finally, the inclusion and integration of a Gordon Research Seminar (GRS) exclusively for postdocs and graduate students prior to the main conference is a particular asset in drawing new scientists into the field and encouraging participation from trainees at all levels. 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.