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.

颅内动脉瘤破裂是非创伤性蛛网膜下腔出血的主要原因。 出血是中风最严重的形式发现防止IA形成的方法可能会极大地 影响患者的生活，但对IA形成的原因和方式的理解有限。该提案旨在确定 通过检测IA形成过程中动脉基因表达来启动IA的分子信号。 血流动力学在IA中起着至关重要的作用。动脉对血流变化的反应是重塑， 基线水平的流体剪切应力，而不损失血管强度和完整性。但在内部审计署，重塑薄， 削弱了动脉壁假设当血流诱导内膜中的内皮细胞， 在媒体中产生导致适应不良反应的信号。在一项概念验证研究中， 使用兔脑动脉显微解剖的RNAseq观察在下丘脑-垂体-肾上腺皮质激素诱导下内膜中的基因表达。 在营养不良性重塑发生的邻近介质中。结果 证明这种方法可以通过鉴定内膜基因揭示IA形成的潜在调节因子， 在新生IA中独特表达，并且其表达与破坏性介质反应相关。 提出了一个全面的筛选基因，控制营养不良的重塑在IA形成。这 将使用兔子模型进行，其中颈动脉结扎增加了后动脉的流量， 循环，导致基底动脉的建设性扩大，同时在基底动脉末端形成IA。基因 通过激光显微切割基底动脉的内膜和中膜中的RNAseq测量表达 将比较来自结扎和未结扎兔的转录组，以鉴定流动诱导的 变化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 营养不良性颅内动脉重塑然后对内膜和中膜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，BMP 2是IA形成的信号之一。为了测试这一点，兔子将被处理 与JL 5，BMP 2受体活性的抑制剂，而IA是由颈动脉结扎诱导。将对组织进行评估 对于（a）使用RNAseq的作为囊性重塑特征的中间基因的表达，和（B） 组织学上确定的囊性损伤的开始。据预测，破坏BMP 2信号传导 该途径将防止培养基中的营养不良反应并抑制流动诱导的IA引发的损伤。 该项目将确定在病理性重塑过程中特异性发挥作用的调节途径， 内部审计处。此外，它将提供营养和营养不良过程中基因表达的前所未有的表征， 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，并可能最终导致 临床缓解IA的药物干预。