The Role of Podosomes in Cerebrovascular Integrity and Intracranial Aneurysm

足体在脑血管完整性和颅内动脉瘤中的作用

• 批准号: 10586672
• 负责人: Zhen Xu
• 金额: $ 39万
• 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 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586672
• 关键词: Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Area; Arteries; Blood Vessels; Blood flow; Brain; Brain Aneurysms; Cause of Death; Cells; Cerebrovascular system; Cessation of life; Circle of Willis; Data; Development; Dilatation - action; Disease; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Extracellular Matrix Degradation; FDA approved; FYN gene; Friction; Functional disorder; Goals; Growth; Growth and Development function; Health Care Costs; Hospitalization; Hospitals; Human; Impairment; Independent Living; Intervention; Intracranial Aneurysm; Knowledge; Link; Lytic; Mechanics; Mission; Molecular; Monomeric GTP-Binding Proteins; Mus; Operative Surgical Procedures; Organelles; PTPN12 gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Public Health; Research; Resolution; Risk Factors; Role; Rupture; Ruptured Aneurysm; SH3 Domains; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Stroke; Subarachnoid Hemorrhage; Survivors; Testing; United States; United States National Institutes of Health; Vascular Endothelium; Vascular Permeabilities; Work; Zebrafish; brain endothelial cell; burden of illness; cerebrovascular; clinical risk; disability; experimental study; gain of function; in vivo; inhibitor; innovation; kinase inhibitor; loss of function; mouse model; new therapeutic target; novel; novel therapeutics; pharmacologic; prevent; response; scaffold; shear stress; single molecule; src-Family Kinases; stroke patient; therapeutic target; translational potential

PROJECT SUMMARY An intracranial aneurysm (IA) is a focal dilatation of an arterial blood vessel in the brain. The rupture of IA causes subarachnoid hemorrhage (SAH), which is the most devastating form of stroke. Due to aneurysmal SAH, around one-third of aneurysm patients will die before reaching the hospital and half of the survivors will never return to independent living. In the United States, around 30,000 people annually suffer a ruptured IA. Unfortunately, there are no drugs available to treat IA except for invasive surgical options, which produce much higher health care costs and are associated with multiple hospitalizations. Therefore, new therapeutic targets are urgently needed as non-invasive alternatives to prevent aneurysmal rupture. However, such attempts have been greatly impeded by a lack of knowledge about the pathogenic and cellular mechanisms that contribute to IA disease. High wall shear stress (HWSS) directly acts on the endothelium of vascular wall as a result of blood flow and is a well- known clinical risk factor for IA disease. The casual role of HWSS in IA pathogenesis has been validated in multiple animal models. However, the molecular basis for HWSS-induced IA development is largely unknown. Interestingly, we observed that HWSS stimulates the assembly of podosomes in the endothelial cells that are subcellular organelles with the ability to degrade extracellular matrix. Based on our preliminary data, we hypothesize that podosome formation and function contributes to IA development and growth under HWSS conditions, and anti-podosome therapy may provide a beneficial effect on IA disease. To test this hypothesis, we will carry out the following specific aims: 1) dissect the molecular mechanisms of HWSS-induced podosome formation and maturation; 2) determine the role of HWSS-induced podosome formation and function in cerebrovascular integrity and IA development and growth. To our knowledge, our proposal is the first to connect podosomes to cerebrovascular integrity, providing a novel mechanism for IA pathogenesis and highlighting a unique anti-podosome therapy for IA disease. Importantly, podosome formation and function can be effectively blocked by SRC kinase inhibitors, which have been intensively developed, including multiple FDA-approved drugs. This fact also makes our study of translational potential for IA disease, or for many other diseases due to the loss of vascular integrity.

项目总结 颅内动脉瘤(IA)是指大脑中动脉血管的局限性扩张。自闭症破裂的原因 蛛网膜下腔出血(SAH)，这是最具破坏性的中风形式。由于动脉瘤性蛛网膜下腔出血， 三分之一的动脉瘤患者在到达医院前就会死亡，而一半的幸存者将永远不会再回到医院. 独立生活。在美国，每年约有3万人患有IA破裂。不幸的是，在那里 除了侵入性手术选择外，是否没有治疗IA的药物可用，这将产生更高的医疗保健 费用，并与多次住院有关。因此，迫切需要新的治疗靶点。 作为预防动脉瘤破裂的非侵入性替代方案。然而，这种尝试受到了极大的阻碍。 由于缺乏对导致IA疾病的致病机制和细胞机制的了解。高墙 切应力(HWSS)是血液流动的结果，直接作用于血管壁内皮细胞，是一种重要的生物力学指标。 已知的IA病的临床危险因素。HWSS在IA发病机制中的偶然作用已在 多种动物模型。然而，HWSS诱导的IA发生的分子基础在很大程度上是未知的。 有趣的是，我们观察到HWSS刺激内皮细胞中的足体组装 具有降解细胞外基质能力的亚细胞细胞器。根据我们的初步数据，我们 在HWSS条件下，足体的形成和功能有助于IA的发育和生长的假设 条件和抗足体治疗可能为IA病提供有益的效果。为了检验这一假设， 我们将开展以下具体工作：1)剖析HWSS诱导的足体的分子机制 2)确定HWSS诱导的足体形成和功能在 脑血管完整性与IA的发展和成长。据我们所知，我们的提案是第一个将 足体对脑血管完整性的影响，为IA的发病机制提供了新的机制，并突出了 针对IA病的独特的抗足类药物治疗。重要的是，足体的形成和功能可以有效地 被密集开发的SRC激酶抑制剂阻止，包括FDA批准的多个 毒品。这一事实也使得我们对IA病或许多其他疾病的翻译潜力的研究 血管完整性的丧失。