PROJECT SUMMARY An intracranial aneurysm (IA) is a bulge or ballooning of the cerebral artery due to weakness in the blood vessel wall. IA rupture causes subarachnoid hemorrhage (SAH), the most life-threatening form of stroke. However, the molecular mechanisms underlying IA pathogenesis are poorly understood, which greatly impedes the identification of therapeutic targets. To date, no pharmacological treatment is available for IA except for invasive surgical options, such as surgical clipping and endovascular coiling, both of which are generally associated with high hospitalization costs. Our long-term goal is to elucidate the molecular mechanisms of IA and develop new therapeutic avenues for this devastating disease. The overall objective in this application is to determine the role of selective autophagy of endothelial focal adhesion (FA) in cerebrovascular integrity and IA formation and progression. The central hypothesis is that p62- VASP interaction is a critical cargo recognition mechanism for selective autophagy of FA (FA-phagy) in endothelial cells, which impairs cerebrovascular integrity and contributes to IA formation and progression. The central hypothesis will be tested in two specific aims: 1) dissect the molecular mechanisms of FA- phagy in endothelial cells; and 2) determine the role of endothelial FA-phagy in cerebrovascular integrity and IA formation and progression. Our proposal is innovative, because we are the first to identify p62- VASP interaction as a novel cargo recognition mechanism for endothelial FA-phagy, and provide endothelial FA-phagy as a novel pathogenic mechanism for IA. The proposed research is significant because we connect selective autophagy to cerebrovascular integrity, which will not only add cutting- edge knowledge to the selective autophagy field but also provide anti-FA-phagy strategy as a novel therapy for IA disease or potentially for many other diseases that exhibit the loss of vascular integrity.