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.

项目摘要 颅内动脉瘤破裂 (IA) 是非创伤性蛛网膜下腔的主要原因 出血是最严重的中风形式，找到预防 IAs 形成的方法可能会显着改善。 影响患者的生活，但对 IAs 形成原因和方式的了解有限。该提案旨在确定。 通过检查 IA 形成过程中的动脉基因表达来启动 IAs 的分子信号。 血流动力学在 IAs 中发挥着至关重要的作用。动脉通过重塑来响应血流变化以保持稳定。 流体剪切应力保持在基线水平，不会损失血管强度和完整性，但在 IAs 中，重塑会变薄和变薄。 当血流诱导内膜中的内皮细胞形成 IAs 时，会削弱动脉壁。 在一项概念验证研究中，研究人员产生了导致媒体适应不良反应的信号。 使用 RNAseq 显微解剖兔脑动脉来观察内膜中的基因表达 动脉瘤诱导血流，以及发生营养不良重塑的邻近介质。 证明这种方法可以通过识别内膜基因来揭示 IA 形成的潜在调节因子 在新生 IAs 中独特表达，其表达与破坏性内侧反应相关。 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选。 将使用兔子模型来完成，其中颈动脉的结扎增加了后部的血流 循环，导致基底动脉建设性扩张，同时在基底动脉末端形成 IA。 将通过 RNAseq 测量从基底动脉激光显微切割的内膜和中膜中的表达 和末端，以及来自结扎和未结扎兔子的转录组将被比较，以识别流诱导的 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。 然后将对内膜和内侧基因对进行相关性分析。 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，将对兔子进行治疗。 使用 BMP2 受体活性抑制剂 JL5，同时评估颈动脉结扎诱导的 IAs。 (a) 使用 RNAseq 表达动脉瘤重塑特征的内侧基因，以及 (b) 根据组织学结果预测，BMP2 信号传导受到破坏。 途径将防止介质中的营养不良反应并抑制流动诱导的 IA 引发损伤。 该项目将确定在病理重塑过程中具体发挥作用的调控途径，从而导致 此外，它将提供营养和营养不良期间基因表达的前所未有的表征。 了解血管对血流反应背后的分子机制将有助于了解动脉重塑。 预防和治疗病理重塑事件的策略，并最终可能导致 临床缓解 IAs 的药物干预。