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.