Role of Selective Autophagy of Focal Adhesion in Intracranial Aneurysm

项目摘要 颅内动脉瘤（IA）是由于血液薄弱而导致的脑动脉隆起或膨胀 血管壁IA破裂导致蛛网膜下腔出血（SAH），这是最危及生命的中风形式。 然而，IA发病机制的分子机制知之甚少， 阻碍了治疗靶点的鉴定。到目前为止，没有药物治疗可用于 IA，但侵入性手术选项除外，如手术夹闭和血管内弹簧圈栓塞，两者均 通常与高昂的住院费用有关。我们的长期目标是阐明 IA的机制，并为这种毁灭性的疾病开发新的治疗途径。整体 本申请的目的是确定选择性自噬在内皮粘着斑中的作用 (FA)在脑血管完整性和IA形成和进展中的作用。核心假设是p62- VASP相互作用是FA选择性自噬（FA-吞噬）的关键货物识别机制， 内皮细胞，其损害脑血管的完整性并有助于IA的形成和进展。 中心假设将在两个特定的目标进行测试：1）剖析FA的分子机制， 内皮细胞中的吞噬; 2）确定内皮FA-吞噬在脑血管完整性中的作用 以及IA的形成和进展。我们的建议是创新的，因为我们是第一个鉴定出p62- VASP相互作用作为内皮FA-吞噬的新型货物识别机制，并提供 内皮FA-吞噬作为IA的新致病机制。所提出的研究是有意义的 因为我们将选择性自噬与脑血管完整性联系起来，这不仅会增加切割， 边缘知识的选择性自噬领域，但也提供了抗FA-吞噬策略作为一种新的 用于IA疾病或潜在地用于表现出血管完整性丧失的许多其他疾病的治疗。

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.