PROJECT DESCRIPTION Cyclic adenosine monophosphate (cAMP) signaling regulates diverse pathways and cellular functions that result in specific responses when compartmentalized. However, the role of cAMP in cilia function is poorly understood, despite the implication of cAMP in the development of ciliopathies. Using two novel techniques, nanoparticle drug delivery and a single-cell imaging system, our preliminary data indicate that changes in cAMP within a cilium could be independent from those in the cytosol. Furthermore, we have preliminary evidence that inhibition of phosphodiesterase-3 (PDE3), an inactivator of cAMP, can restore ciliary function in ciliopathy models that are prone to aneurysm, and that aneurysmal vessels are characterized by genomic instability. Here, we hypothesize that ciliary cAMP plays an important role in aneurysm formation, and we propose to test if PDE3 is involved in vascular aneurysm via genomic instability (Aim 1) and clarify its role in cAMP signaling in primary cilia (Aim 2). Overall, we will test the idea if a single cilium could be a critical sensor acting as a responsive PDE/cAMP compartment.