Project Summary/Abstract The 2024 Gordon Research Conference on Cyclic Nucleotide Phosphodiesterases (PDEs) will explore bleeding-edge research driving the field to reconceptualize the fundamental biology and therapeutic potential of targets within the cAMP/cGMP cyclic nucleotide signaling cascades. These pathways, which are regulated by PDEs, modulate a number of critical physiological processes across the lifespan. As such, targets within these signaling cascades have long been of high interest to drug discovery efforts, particularly in the context of aging-related diseases. Indeed, we are seeing the fruits of our labor with many PDE inhibitors in the clinic today and many more in active clinical trials. The program will include state-of-the-art approaches that shed new light on the physiology of these cascades and reveal sophisticated mechanisms by which targets may be manipulated for therapeutic gain. A fresh systems-level approach will be taken, with a given session focusing on the same target in the context of different organs/diseases. By bringing together academic and industrial scientists at all career stages from the fields of aging, cancer, cardiology, immunology & inflammation, neuroscience/psychiatry, pulmonology, etc., the conference hopes to advance drug discovery efforts by stimulating deep discussion of the potential for efficacy versus side effects. The GRC will include 62 speakers (54 invited and 8 chosen from abstracts) and 2 interactive poster sessions. We invited such a high proportion of our speakers to dramatically increase the diversity of our speaker pool (51.6% female, 14.5% underrepresented minority by NIH and/or GRC definitions, 21% trainees). The pre-meeting seminar (GRS) will have further talk and poster opportunities for undergraduate and graduate students, post-bacs, and post-docs, as well as a career/mentoring panel. A ‘Power Hour’ in the main meeting will focus on addressing ways we all can improve diversity and inclusion in science. We aim to foster an interactive, friendly environment in which ideas can be freely exchanged independently of background or seniority. The GRC program will be organized into nine morning and evening sessions entitled: (1) What we thought we knew and what (we think) we know now, (2) Shining a light on cyclic nucleotide signaling pathways: advancements in biosensors and structure, (3) The 'ins' and 'outs' of cyclic nucleotide signaling: intracellular cyclases and extracellular cyclic nucleotide signaling, (4) Do unto those downstream as you would have those upstream do unto you: cyclic nucleotide effectors, (5) Buggin' out with cyclic nucleotide signaling: non-mammalian PDEs, (6) 1 is not the loneliest number: PDE1, PDE10, and PDE11, (7) Why are we so scared? Because PDE7, 8, 9, (8) The most explored: PDE4, and (9) To cross or not to cross the streams, that is the question: PDE2 and PDE3 crosstalk. With afternoons dedicated to social activities that facilitate networking and idea exch...