Deciphering the regulatory role of matricelluar protein CCN3 in functional collateral blood flow

解读基质细胞蛋白CCN3在功能性侧支血流中的调节作用

基本信息

批准号：
10594955
负责人：
Zhiyong Lin
金额：
$ 51.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594955
关键词：
Address Adult Affect Amputation Animal Model Area Automobile Driving Biological Process Blood Vessels Blood flow Cells Clinical Combined Modality Therapy Competence Data Development Diabetic mouse Disease Disease Progression Endothelial Cells Endothelium Extracellular Matrix Failure Functional disorder Glean Healthcare Hindlimb Homeostasis Hypoxia Impairment Inbred BALB C Mice Ischemia Knock-out Knockout Mice Knowledge Laboratories Limb structure Mediating Medical Modeling Molecular Morbidity - disease rate Mus Muscle function Necrosis Operative Surgical Procedures Pathogenesis Pathology Patients Perfusion Peripheral arterial disease Phenocopy Phenotype Physiological Play Pre-Clinical Model Process Production Protein Family Proteins Recovery Regulation Reperfusion Therapy Resources Role Signal Pathway Signal Transduction Signaling Molecule Therapeutic Tissues Tube VEGFA gene Vascular Endothelial Growth Factors Vascularization angiogenesis cell type clinical development conditional knockout critical limb Ischemia design disease phenotype experimental study functional disability functional loss impaired driving performance in vivo insight limb ischemia member migration mortality neovascularization novel novel strategies novel therapeutics overexpression pharmacologic protein function response

项目摘要

PROJECT SUMMARY Peripheral artery disease (PAD) affects more than 200 million adults worldwide. Critical limb ischemia (CLI), the most advanced form of PAD, causes significant morbidity, mortality, and health care resource utilization. Despite our increased understanding of the pathobiology of PAD, medical treatments remain inadequate and revascularization (surgical and non-surgical) or amputation are unfortunately the major therapeutic options. Therefore, it is imperative to address this important unmet clinical need, potentially by the development of novel pharmacologic therapies combined with more effective management strategies. However, current efforts in these areas are significantly hindered due to incomplete knowledge of the fundamental mechanisms that govern the dysregulation of vascular function, as well as the failure to generate an effective vascular network to restore flow. Our recent observations have identified CCN3 (Nov), a specific member of the matricellular protein family, CCN (Cyr61, Ctgf, Nov), as an important regulator of endothelial function in the context of neovascularization. CCN3 expression was found to be strongly reduced in limb tissues from CLI patients. In a murine hind limb ischemia (HLI) model, global CCN3 deficiency resulted in enhanced necrosis concomitant with decreases in tissue reperfusion, hypoxia-induced factor (HIF) signaling and VEGF-A production - key mechanisms responsible for the loss of functional collateral blood flow in PAD. Additionally, cell-type specific deletion of CCN3 in mice and preliminary cell-based studies indicate that endothelial cell CCN3 deficiency plays a major role in the impairment of blood flow recovery. Restrictive deletion of CCN3 in the endothelium phenocopies the effects of the global CCN3 knockout. This strongly suggests that endothelial CCN3 is a positive regulator of collateral blood flow recovery following HLI. At the cellular level, loss of CCN3 results in impaired endothelial migration and tube formation, pivotal processes involved in angiogenesis requisite for blood flow recovery. Collectively, these observations led to the central hypothesis that CCN3 serves as a critical physiological regulator in driving neovascularization and the attendant tissue perfusion. In Aim 1, we will fully characterize the role of CCN3 in the regulation of collateral blood flow. Aim 2 is designed to elucidate the mechanisms by which CCN3 deficiency leads to compromised neovascularization and collateral blood flow. Finally, in Aim 3, we plan to explore the therapeutic potential of CCN3 in preclinical models of limb ischemia. The results of these studies will elucidate the role of CCN3 in controlling endothelial function in ischemia and the mechanisms underlying its ability to promote neovascularization and functional collateral blood flow.

项目概要外周动脉疾病 (PAD) 影响着全球超过 2 亿成年人。严重肢体缺血（CLI）， PAD 的最高级形式，导致显着的发病率、死亡率和医疗资源利用率。尽管我们对 PAD 病理学的了解不断加深，但医疗治疗仍然不足，而且不幸的是，血运重建（手术和非手术）或截肢是主要的治疗选择。因此，必须解决这一重要的未满足的临床需求，可能通过开发新的药物疗法与更有效的管理策略相结合。然而，目前由于对基本机制的了解不完整，这些领域的努力受到严重阻碍控制血管功能失调，以及无法产生有效的血管网络恢复流量。我们最近的观察发现了 CCN3（11 月），它是基质细胞蛋白家族 CCN (Cyr61, Ctgf, Nov)，作为内皮功能的重要调节因子新生血管形成的背景。 CLI 发现肢体组织中 CCN3 表达显着降低患者。在小鼠后肢缺血 (HLI) 模型中，整体 CCN3 缺乏导致坏死加剧伴随组织再灌注、缺氧诱导因子 (HIF) 信号传导和 VEGF-A 的减少产生——导致 PAD 功能性侧支血流丧失的关键机制。此外，小鼠中 CCN3 的细胞类型特异性缺失和初步细胞研究表明内皮细胞 CCN3 缺乏在血流恢复受损中起着重要作用。限制性删除CCN3 内皮表型复制了全局 CCN3 敲除的影响。这强烈表明内皮细胞 CCN3 是 HLI 后侧支血流恢复的正调节因子。在细胞水平上，CCN3 的缺失导致内皮迁移和管形成受损，这是血管生成的关键过程血流恢复的必要条件。总的来说，这些观察结果得出了一个中心假设：CCN3 作为驱动新血管形成和随之而来的组织灌注的关键生理调节剂。在目标1，我们将充分表征CCN3在侧支血流调节中的作用。目标2已设计阐明 CCN3 缺乏导致新血管形成受损的机制侧支血流。最后，在目标 3 中，我们计划探索 CCN3 在临床前的治疗潜力肢体缺血模型。这些研究的结果将阐明CCN3在控制中的作用缺血中的内皮功能及其促进新生血管形成的机制功能性侧支血流。