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.

项目摘要 颅内动脉瘤（IA）是脑内动脉血管的局灶性扩张。IA破裂导致 蛛网膜下腔出血（SAH），这是最具破坏性的中风形式。由于严重SAH， 三分之一的动脉瘤患者会在到达医院之前死亡，一半的幸存者将永远不会回到医院。 独立生活。在美国，每年约有30，000人患有IA破裂。可惜 除了可产生更高医疗保健的侵入性手术选择外，没有药物可用于治疗IA 费用，并与多次住院有关。因此，迫切需要新的治疗靶点 作为非侵入性的替代方案，以防止动脉瘤破裂。然而，这种尝试受到了很大的阻碍， 缺乏对IA疾病的致病和细胞机制的了解。高墙 切应力（shear stress，HWSS）作为血流的结果直接作用于血管壁的内皮，并且是良好的， IA疾病的已知临床风险因素。HWSS在IA发病机制中的偶然作用已在以下研究中得到证实： 多种动物模型。然而，HWSS诱导IA发展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刺激了内皮细胞中的podosomes的组装， 具有降解细胞外基质能力的亚细胞器。根据初步数据，我们 假设在HWSS下，足体形成和功能有助于IA发育和生长 在某些情况下，抗足体疗法可以对IA疾病提供有益的效果。为了检验这一假设， 本研究的具体目的是：1）探讨HWSS诱导足体形成的分子机制 2）确定HWSS诱导的足状体形成和功能的作用， 脑血管的完整性和IA的发育和生长。据我们所知，我们的建议是第一个连接 podosomes脑血管的完整性，提供了一个新的机制，IA发病机制，并强调了 针对IA疾病的独特抗足体疗法。重要的是，足体的形成和功能可以有效地 被SRC激酶抑制剂阻断，这些抑制剂已经被大量开发，包括多种FDA批准的 毒品这一事实也使得我们对IA疾病或许多其他疾病的翻译潜力的研究， 血管完整性的丧失