Defining the role of extracellular matrix mechanics in vascular Ehlers-Danlos syndrome

定义细胞外基质力学在血管埃勒斯-当洛斯综合征中的作用

基本信息

批准号：
10387394
负责人：
Elizabeth Louise Doherty
金额：
$ 3.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387394
关键词：
Actins Address Aneurysm Aorta Biological Assay Blood Vessels Cell physiology Cells Clinical Treatment Code Collagen Connective Tissue Diseases Data Development Disease Disease Progression Dissection Ehlers-Danlos Syndrome Endothelial Cells Endothelium Event Extracellular Matrix Extracellular Matrix Proteins FDA approved Failure Family Fibroblasts Focal Adhesions Functional disorder Genes Glycosaminoglycans Harvest Human In Vitro Inflammation Inflammatory Integrins Investigation Lead Link Mechanics Methods Modulus Molecular Mus Mutation Nitric Oxide Pathogenesis Pathologic Pathology Pathway interactions Patients Phenotype Play Prevention Production Property Proteins Public Health Rare Diseases Research Role Route Rupture Ruptured Aneurysm Scanning Electron Microscopy Signal Pathway Signal Transduction Stains Structure System Therapeutic Tissues Translating Variant Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Western Blotting Work crosslink cytokine endothelial dysfunction fibrous protein flexibility genipin in vivo in vivo Model mechanical properties mechanotransduction mortality mouse model nanoindentation novel therapeutics palliative patient response prevent protein expression protein structure response vascular endothelial dysfunction vascular injury viscoelasticity

项目摘要

PROJECT SUMMARY Vascular Ehlers-Danlos syndrome (EDS Type IV, vEDS) is a variant of Ehlers-Danlos syndrome (EDS)—a family of connective tissue disorders with 13 defined subtypes—that is caused by mutations in the COL3A1 gene. These mutations result in reduced collagen III in the vascular ECM and typically leads to aortic dissection and aneurysm, resulting in vessel rupture. In vEDS and other EDS variants there is evidence that ECM content, protein structure, and mechanical properties are altered. Vascular endothelial cells (ECs) sense and respond to ECM composition and mechanical properties, and pathologic changes to ECM, including increased stiffness, can induce effector signaling that results in increased vascular permeability and secretion of factors such as vascular endothelial growth factor and nitric oxide. Such changes in EC phenotype and function, broadly referred to as endothelial dysfunction and can contribute to vascular diseases, such as in aneurysm formation. I hypothesize that mutations in the COL3A1 gene alter ECM mechanical properties, as a result of protein content and structural changes in the ECM, which leads to EC dysfunction and results in weakened vasculature. I will address this hypothesis with three aims using a combination of in vitro and in vivo methods. In Aim 1, I will address the impact of COL3A1 mutations on ECM composition and mechanical properties using cell-derived matrix (CDM) from vEDS patient-derived cells in vitro to determine how mutations in COL3A1 alter elastic and viscoelastic properties of ECM. In Aim 2, I will address how changes in mechanical properties of vEDS CDM relates to vascular EC phenotype and function. I will analyze endothelial cell response to vEDS CDM with varying stiffness to decouple ECM protein content and mechanics to define specific mechanisms by which pathologic CDM influences endothelial cell phenotype and vascular barrier function. In Aim 3, I will address the impact of both endothelial dysfunction and changes in ECM mechanical properties on disease progression in vivo. I will use an established mouse model of vEDS to investigate both endothelial cell phenotype and ECM mechanics in addition to vascular rupture events and overall tissue fragility to probe the link between changes in EC phenotype and aortic mechanical failure. This proposed work will identify how compromised ECM mechanical properties impact vEDS disease manifestation through the probing of endothelial cell signaling pathways related to vascular function, inflammation, and mechanotransduction. A better understanding of these pathways will lead to new routes of treatment for vEDS patients – of which there are none currently approved by the FDA. Further, these mechanisms of failure are likely more broadly relevant for aneurysm formation and progression in general (not just in vEDS patients) and may be of help for furthering research of identifying, treating, and preventing aneurysms.

项目概要血管埃勒斯-当洛斯综合征（EDS IV 型，vEDS）是埃勒斯-当洛斯综合征 (EDS) 的一个变种——一个家族具有 13 种明确亚型的结缔组织疾病——由 COL3A1 基因突变引起。这些突变导致血管 ECM 中的胶原蛋白 III 减少，通常会导致主动脉夹层和动脉瘤，导致血管破裂在 vEDS 和其他 EDS 变体中，有证据表明 ECM 含量，蛋白质结构和机械特性发生改变，血管内皮细胞 (EC) 能够感知并做出反应。 ECM 成分和机械性能，以及 ECM 的病理变化，包括刚度增加、可以诱导效应信号传导，导致血管通透性增加和因子分泌，例如血管内皮生长因子和一氧化氮的这种变化广泛地称为EC表型和功能。内皮功能障碍可能导致血管疾病，例如动脉瘤形成。清除 COL3A1 基因突变会因蛋白质含量而改变 ECM 机械性能以及 ECM 的结构变化，这会导致 EC 功能障碍并导致脉管系统减弱。在目标 1 中，我将结合体外和体内方法通过三个目标来解决这一假设。使用细胞衍生的方法解决 COL3A1 突变对 ECM 成分和机械性能的影响来自 vEDS 患者体外细胞的基质（CDM），以确定 COL3A1 突变如何改变弹性和 ECM 的粘弹性特性在目标 2 中，我将讨论 vEDS CDM 的机械特性如何变化。与血管 EC 表型和功能相关我将分析内皮细胞对不同 vEDS CDM 的反应。刚度可解耦 ECM 蛋白质含量和力学，以定义病理学的具体机制 CDM 影响内皮细胞表型和血管屏障功能在目标 3 中，我将讨论 CDM 的影响。我将研究内皮功能障碍和 ECM 机械特性的变化对体内疾病进展的影响。使用已建立的 vEDS 小鼠模型来研究内皮细胞表型和 ECM 力学除了血管破裂事件和整体组织脆性之外，还探讨 EC 表型变化之间的联系和主动脉机械故障。这项拟议的工作将确定 ECM 机械性能如何受到损害。通过探测与血管相关的内皮细胞信号通路影响 vEDS 疾病表现功能、炎症和机械转导的更好理解将带来新的结果。 vEDS 患者的治疗途径 - 目前尚无 FDA 批准的途径。失败的机制可能与动脉瘤的形成和进展有更广泛的相关性（不是仅适用于 vEDS 患者），可能有助于进一步研究识别、治疗和预防动脉瘤。