Hemodynamically induced molecules regulating the initiation of intracranial aneurysms

血流动力学诱导分子调节颅内动脉瘤的发生

• 批准号: 10592695
• 负责人: JOHN P KOLEGA
• 金额: $ 43.88万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592695
• 关键词: Affect; Age; American; Aneurysm; Animal Model; Arteries; Automobile Driving; Autopsy; BMP2 gene; Bilateral; Biochemistry; Blood Circulation; Blood Vessels; Blood flow; Brain; Brain Aneurysms; Carotid Arteries; Case Study; Cell Proliferation; Cellular biology; Cerebrovascular Circulation; Cerebrum; Characteristics; Circle of Willis; Clinical; Coupled; Distal; Endothelial Cells; Endothelium; Event; Excision; Extracellular Matrix Degradation; Gender; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Growth; Growth Factor; Histologic; Histology; Human; Hypertension; Intervention; Intracranial Aneurysm; Investigation; Lasers; Lead; Lesion; Ligation; Liquid substance; Location; Measures; Medial; Modeling; Molecular; Oryctolagus cuniculus; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmacology; Play; Prevention; Prevention strategy; Process; Regulatory Pathway; Research Personnel; Risk; Role; Rupture; Ruptured Aneurysm; Signal Pathway; Signal Transduction; Site; Smoking; Stroke; Structure; Survivors; System; Testing; Thinness; Tissues; Vascular remodeling; Work; arterial remodeling; basilar artery; behavioral construct; cerebral artery; hemodynamics; inhibitor; insight; intima media; lifestyle intervention; neurosurgery; novel strategies; prevent; receptor; response; shear stress; transcriptome; transcriptome sequencing

Project Summary Ruptured intracranial aneurysms (IAs) are the main cause of non-traumatic subarachnoid hemorrhage, the most severe form of stroke. Discovering ways to prevent IAs from forming could dramatically impact patients’ lives, but understanding of why and how IAs form is limited. This proposal aims to identify molecular signals that initiate IAs by examining arterial gene expression during IA formation. Hemodynamics play a crucial role in IAs. Arteries respond to changes in blood flow by remodeling to keep fluid shear stress at baseline levels without loss of vessel strength and integrity. But in IAs, remodeling thins and weakens the arterial wall. It is hypothesized that IAs form when flow induces endothelial cells in the intima to produce signals that cause maladaptive responses in the media. In a proof-of concept study, the investigators used RNAseq of microdissected cerebral arteries in rabbits to observe gene expression in the intima under aneurysm-inducing flow, and in the contiguous media where dystrophic remodeling occurs. The results demonstrated that this approach can reveal potential regulators of IA formation by identifying intimal genes that are uniquely expressed in nascent IAs and whose expression correlates with destructive medial responses. A comprehensive screen is proposed for genes that control dystrophic remodeling during IA formation. This will be done using a rabbit model, in which ligation of the carotid arteries increases flow in the posterior circulation, causing constructive enlargement of the basilar artery while an IA forms at the basilar terminus. Gene expression will be measured by RNAseq in intima and media that are laser microdissected from the basilar artery and terminus, and transcriptomes from ligated and unligated rabbits will be compared to identify flow-induced changes. Changes at the basilar terminus will be compared with the basilar artery to reveal genes that are unique to dystrophic IA remodeling. Correlation analysis will then be performed on intimal and medial gene pairs to detect potential signal-response relationships. Preliminary studies suggest that BMP2 is one such signal for IA formation. To test this, rabbits will be treated with JL5, an inhibitor of BMP2-receptor activity, while IAs are induced by carotid ligation. Tissues will be assessed for (a) expression of medial genes that are characteristic of aneurysmal remodeling, using RNAseq, and (b) initiation of aneurysmal damage, as determined histologically. It is predicted that disrupting the BMP2 signaling pathway will prevent dystrophic responses in the media and inhibit flow-induced IA-initiating damage. This project will identify regulatory pathways acting specifically during pathological remodeling that leads to IAs. In addition, it will provide unprecedented characterization of gene expression during trophic and dystrophic arterial remodeling. Understanding the molecular mechanisms behind vascular responses to flow will inform strategies for prevention and treatment of pathological remodeling events, and could ultimately lead to pharmacological interventions for clinical mitigation of IAs.

破裂的颅内动脉瘤(IAS)是非外伤性蛛网膜下腔的主要原因 出血，中风最严重的形式。发现防止IAS形成的方法可以极大地 影响了患者的生活，但对IAS形成的原因和方式的了解有限。这项提案旨在确定 在IA形成过程中，通过检测动脉基因表达来启动IAS的分子信号。 血流动力学在IAS中起着至关重要的作用。动脉对血流变化的反应是通过重塑来保持 在不损失血管强度和完整性的情况下，基线水平上的流体剪切应力。但在国际会计准则中，改建变薄了 削弱动脉壁。推测当血流诱导内膜内皮细胞产生IAS时， 产生在媒体中引起不适应反应的信号。在一项概念验证研究中，研究人员 应用显微解剖兔脑动脉RNAseq技术观察血管内膜基因表达 导致动脉瘤的血流，以及发生营养不良重塑的邻近中层。结果是 证明这种方法可以通过识别内膜基因来揭示IA形成的潜在调节因素 在新生的IAS中唯一表达，其表达与破坏性的中间反应相关。 建议对IA形成过程中控制营养不良重塑的基因进行全面筛查。这 将使用兔模型来完成，在该模型中，结扎颈动脉增加后部血流量 循环，导致基底动脉建设性扩张，而在基底动脉末端形成IA。基因 RNAseq将测量激光显微切割的基底动脉内膜和中膜的表达 和末端，以及结扎和未结扎的兔的转录本进行比较，以确定流诱导 改变。基底动脉末端的变化将与基底动脉进行比较，以揭示独特的基因 营养不良的IA重塑。然后对内膜和中膜基因对进行相关性分析，以 检测潜在的信号-响应关系。 初步研究表明，BMP2是IA形成的信号之一。为了测试这一点，兔子将接受治疗 使用BMP2受体活性抑制剂JL5，而颈动脉结扎诱导IAS。将对组织进行评估 (A)使用RNAseq，表达具有动脉瘤样重塑特征的中间基因，以及(B) 组织学上确定的动脉瘤性损害的开始。据预测，干扰BMP2信号转导 途径将防止营养不良反应在介质中，并抑制流诱导的IA启动损伤。 该项目将确定在病理重塑过程中特定作用的调控通路，从而导致 国际会计准则。此外，它还将提供营养不良和营养不良期间基因表达的前所未有的特征。 动脉重塑。了解血管对血流反应背后的分子机制将有助于 预防和治疗病理性重塑事件的策略，并最终可能导致 临床缓解IAS的药物干预。