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.

项目摘要破裂的颅内动脉瘤（IAS）是非创伤性蛛网膜下腔的主要原因 出血，最严重的中风形式。发现防止IAS形成的方法可能会急剧 影响患者的生命，但了解IAS的原因和方式有限。该建议旨在确定 通过检查IA形成过程中的伪影基因表达来启动IAS的分子信号。 血液动力学在IAS中起着至关重要的作用。动脉通过重塑来应对血流的变化以保持 流体剪切应力在基线水平下而不会损失容器强度和完整性。但是在IAS中，重塑细微和 削弱了动脉壁。假设流动诱导内膜中的内皮细胞时形成IAS 产生在媒体中引起不良适应反应的信号。在一项概念验证研究中，研究人员 在兔子中使用的微解剖脑动脉的RNASEQ观察在内膜下的基因表达 动脉瘤诱导的流动，以及发生营养不良重塑的连续培养基。结果 证明这种方法可以通过识别内膜基因来揭示IA形成的潜在调节剂 在新生的IAS中独特地表达，其表达与破坏性媒体反应相关。 对于控制IA形成过程中营养不良重塑的基因，提出了一个全面的屏幕。这 将使用兔模型进行，其中颈动脉的连接会增加后部的流动 循环，导致基底动脉的建设性扩张，而基底末端的IA形成。基因 表达将通过rnaseq在Intima和培养基中测量，这些介质是从基底动脉微切除的激光器 将比较末端以及连接和无缘兔的转录组，以识别流动诱导的 更改。基底末端的变化将与基底动脉进行比较，以揭示独特的基因 进行营养不良的IA重塑。然后，将对内膜和内侧基因对进行相关分析至 检测潜在的信号响应关系。 初步研究表明，BMP2就是IA形成的一种信号。为了测试这一点，兔子将被治疗 与BMP2受体活性抑制剂JL5一起使用，而IAS则是由颈动脉连接诱导的。将评估组织 对于（a）使用RNASEQ和（b）的动脉瘤重塑的特征的培养基基因表达 在组织学上确定的动脉瘤损伤的启动。可以预测破坏BMP2信号传导 途径将防止培养基中营养不良的反应，并抑制流动引起的IA发射损伤。 该项目将确定在病理重塑期间专门起作用的调节途径，这导致 IAS。此外，它将在营养和营养不良期间提供基因表达的前所未有的表征 动脉重塑。了解血管反应背后的分子机制将告知 预防和治疗病理重塑事件的策略，并最终导致 IAS临床缓解的药理干预措施。