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

p62 介导的内皮 FA 吞噬在颅内动脉瘤中的作用

• 批准号: 10574825
• 负责人: Yanning Rui
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574825
• 关键词: Affinity; Aneurysm; Area; Autophagocytosis; Autophagosome; Binding; Biological Assay; Blood Vessels; Brain Aneurysms; CRISPR/Cas technology; Cause of Death; Cerebrovascular system; Cessation of life; Circle of Willis; Clinical Trials; Data; Degradation Pathway; Development; Digestion; Disease; Drug Targeting; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Extravasation; Focal Adhesions; Foundations; Genes; Goals; Health; Human; Impairment; Incidence; Intracranial Aneurysm; Kinetics; Knowledge; Mediating; Methods; Mission; Monitor; Mus; Names; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Permeability; Phosphorylation; Phosphotransferases; Play; Process; Property; Public Health; Receptor Gene; Reporting; Research; Role; Rupture; Stains; Subarachnoid Hemorrhage; System; TANK-binding kinase 1; Testing; Tracer; United States National Institutes of Health; Variant; Vascular Diseases; Vascular Endothelial Cell; Vascular Permeabilities; Work; Zebrafish; brain endothelial cell; burden of illness; cerebrovascular; disability; experimental study; gain of function; improved; in vivo; inhibitor; innovation; knock-down; loss of function; mimetics; mouse model; new therapeutic target; novel; novel therapeutics; preservation; prevent; receptor; receptor function; recruit; stroke patient

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.

项目摘要 颅内动脉瘤（IA）是大脑血管薄弱区域的气球样隆起。 动脉瘤破裂导致蛛网膜下腔出血，这是中风死亡和残疾的主要原因 患者然而，导致IA发展的潜在致病机制尚不清楚， 这极大地阻碍了为该疾病确定新的治疗靶点的尝试。 脑血管完整性在IA的发展中起着关键作用。特别地，粘着斑（FA）， 使内皮细胞能够粘附于其细胞外基质的性质是 脑血管完整性最近，我们将FA-吞噬命名为“FA的选择性自噬”， 调节FA稳定性。此外，我们确定p62是内皮细胞中FA-吞噬的主要货物受体， 细胞我们的中心假设是p62介导的内皮细胞FA-吞噬损害脑血管的完整性 从而有助于IA的发展。这一假设将在两个特定的目标进行测试：1）确定 p62介导内皮细胞FA吞噬在脑血管完整性和颅内动脉瘤中作用 发展;和2）定义p62介导的内皮FA-吞噬中的货物识别机制。 这些拟议的实验可能为进一步治疗IA疾病提供坚实的科学基础， 靶向p62介导的货物识别机制。重要的是，这种目标货物识别 一种机制可能会精确地干扰一种特定类型的自噬，从而改变目前的范式， 血管疾病中的自噬操纵，因为临床试验中的大多数抑制剂都能阻断自噬， 所有类型的自噬都共享核心机制，从而导致不必要的后果。我们 该项目的目标可能共同建立抗FA-吞噬策略作为IA的新疗法，并可能 对于许多其他疾病由于血管完整性的损失。