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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要颅内动脉瘤 (IA) 是大脑中动脉血管的局灶性扩张。 IA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SAH，周围三分之一的动脉瘤患者在到达医院之前就会死亡，一半的幸存者将永远无法返回独立生活。在美国，每年约有 30,000 人患有 IA 破裂。不幸的是，有除了侵入性手术选择之外，没有其他药物可用于治疗 IA，因为侵入性手术可以产生更高的医疗保健效果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，这样的尝试却遭到了极大的阻碍由于缺乏对导致 IA 疾病的致病和细胞机制的了解。高墙剪切应力（HWSS）由于血流直接作用于血管壁内皮，是一种很好的 IA 疾病的已知临床危险因素。 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 IA 发展的分子基础在很大程度上尚不清楚。有趣的是，我们观察到 HWSS 刺激内皮细胞中足体的组装，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，我们假设足体的形成和功能有助于 HWSS 下 IA 的发育和生长抗足体治疗可能对 IA 疾病产生有益作用。为了检验这个假设，我们将实现以下具体目标：1）剖析HWSS诱导足体的分子机制形成和成熟； 2)确定HWSS诱导的足小体形成和功能的作用脑血管完整性和 IA 发育和生长。据我们所知，我们的提案是第一个连接的足体对脑血管完整性的影响，为 IA 发病机制提供了新的机制，并强调了针对 IA 疾病的独特抗足体疗法。重要的是，足小体的形成和功能可以有效地被 SRC 激酶抑制剂阻断，这些抑制剂已被深入开发，包括多种 FDA 批准的药物。这一事实也促使我们研究 IA 疾病或许多其他疾病的转化潜力血管完整性的丧失。