Role of Selective Autophagy of Focal Adhesion in Intracranial Aneurysm

局部粘连选择性自噬在颅内动脉瘤中的作用

• 批准号: 10586692
• 负责人: Yanning Rui
• 金额: $ 38.21万
• 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: 2023-01-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586692
• 关键词: Affect; Affinity; Animal Model; Area; Autophagocytosis; Binding; Biological Assay; Blood Vessels; Brain Aneurysms; Cause of Death; Cells; Cessation of life; Circle of Willis; Complex; Data; Degradation Pathway; Development; Digestion; Disease; Endothelial Cells; Endothelium; Exhibits; Extracellular Matrix; Focal Adhesions; Genes; Genetic; Goals; Growth; Health; Hospital Costs; Impairment; Incidence; Intracranial Aneurysm; Kinetics; Knockout Mice; Knowledge; Life; Link; Mediating; Mission; Molecular; Morphology; Mus; Names; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pharmacological Treatment; Phosphorylation; Play; Process; Public Health; Research; Resolution; Role; Rupture; Ruptured Aneurysm; Series; Stains; Stroke; Subarachnoid Hemorrhage; Surgical Clips; System; Testing; Time; United States National Institutes of Health; Variant; Vascular Permeabilities; Work; Zebrafish; burden of illness; cerebral artery; cerebrovascular; disability; experimental study; gain of function; improved; innovation; knock-down; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; preservation; prevent; receptor; receptor binding; shear stress; single molecule; stroke patient; superresolution microscopy; therapeutic target; vasodilator-stimulated phosphoprotein

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.

项目摘要 颅内动脉瘤（IA）是由于血液无力而导致大脑动脉的隆起或膨胀 船墙。 IA破裂会导致蛛网膜下腔出血（SAH），这是中风的生命最长的形式。 然而，IA发病机理的分子机制知之甚少，这是广泛的 阻碍了治疗靶标的识别。迄今为止，尚无药理学治疗 ia除了侵入性手术选择，例如手术剪裁和血管内卷曲，这两个 通常与高住院费用有关。我们的长期目标是阐明分子 IA的机制并为这种毁灭性疾病开发新的治疗途径。总体 本应用程序中的目的是确定内皮局灶性粘附选择性自噬的作用 （FA）在脑血管完整性和IA形成和进展中。中心假设是p62- VASP相互作用是FA选择性自噬（FA-Phagy）的关键货物识别机制 内皮细胞会损害脑血管完整性，并有助于IA的形成和进展。 中央假设将以两个具体的目的进行检验：1）剖析FA-的分子机制 内皮细胞中的吞噬； 2）确定内皮FA-Phagy在脑血管完整性中的作用 和IA的形成和进展。我们的建议是创新的，因为我们是第一个确定p62-的人 VASP相互作用是一种新型货物识别机制，用于内皮FA-PHAGY，并提供 内皮FA-Phagy是IA的新型致病机制。拟议的研究很重要 因为我们将选择性自噬连接到脑血管完整性，这不仅会增加剪切 - 在选择性自噬领域的边缘知识，但也提供了反粉刺策略作为一种新颖的策略 IA疾病的治疗或许多其他表现出血管完整性丧失的疾病的治疗。