Role of p62-Mediated Endothelial FA-Phagy in Intracranial Aneurysms

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PROJECT SUMMARY An intracranial aneurysm (IA) is a balloon-like bulge in a weakened area of a blood vessel in the brain. Rupture of an IA leads to a subarachnoid hemorrhage, a major cause of death and disability in stroke patients. However, the underlying pathogenic mechanisms that contribute to IA development are poorly understood, which greatly impedes attempts to identify novel therapeutic targets for the disease. Cerebrovascular integrity plays a pivotal role in IA development. In particular, focal adhesion (FA), a property that enables endothelial cells to adhere to their extracellular matrix, is required for cerebrovascular integrity. Recently, we named FA-phagy for “selective autophagy of FA” which can regulate FA stability. Moreover, we identified p62 as the major cargo receptor for FA-phagy in endothelial cells. Our central hypothesis is that p62-mediated endothelial FA-phagy impairs cerebrovascular integrity and thus contributes to IA development. This hypothesis will be tested in two specific aims: 1) determine the role of p62-mediated endothelial FA-phagy in cerebrovascular integrity and intracranial aneurysm development; and 2) define the cargo recognition mechanisms in p62-mediated endothelial FA-phagy. These proposed experiments may provide a firm scientific foundation for further treating IA disease by targeting p62-mediated cargo recognition mechanisms. Importantly, this targeting cargo recognition mechanism may precisely interfere with a specific type of autophagy and thus shift the current paradigm on autophagy manipulation in vascular diseases, since most inhibitors in clinical trials block autophagic core machinery that is shared in all types of autophagy, thus leading to unwanted consequences. Our project's aims may collectively establish anti-FA-phagy strategy as a novel therapy for IA and potentially for many other diseases due to the loss of vascular integrity.