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.

项目摘要周围动脉疾病（PAD）影响全球超过2亿成人。关键的肢体缺血（CLI），最先进的PAD形式会引起大量发病率，死亡率和医疗资源利用率。尽管我们对PAD病理生物学的了解越来越多，但医疗疗法仍然不足和不幸的是，血运重建（手术和非手术）或截肢是主要的治疗选择。因此，必须通过发展新型药理学疗法与更有效的管理策略相结合。但是，当前由于对基本机制的了解不完整，因此在这些领域的努力受到了极大的阻碍控制血管功能的失调以及无法产生有效血管的失调恢复流量的网络。我们最近的观察结果已经确定了CCN3（NOV），母细胞蛋白家族，CCN（CYR61，CTGF，NOV），作为内皮功能的重要调节剂新血管形成的背景。发现CCN3表达在CLI的肢体组织中大大降低患者。在鼠后肢缺血（HLI）模型中，全局CCN3缺乏导致坏死增强与组织再灌注，缺氧诱导的因子（HIF）信号传导和VEGF-A的伴随性降低生产 - 负责PAD中功能性附带血流损失的关键机制。此外， CCN3在小鼠和基于细胞的初步研究中的细胞类型特异性缺失表明内皮细胞 CCN3缺乏在血流恢复损害中起主要作用。 CCN3的限制性删除内皮表，全球CCN3敲除的影响。这强烈表明内皮 CCN3是HLI后副血流恢复的积极调节剂。在细胞水平上，CCN3的丢失结果导致内皮迁移和管形成受损，涉及血管生成的关键过程血流恢复的必要条件。总的来说，这些观察结果导致了CCN3的中心假设在推动新血管形成和随之而来的组织灌注方面是关键的生理调节剂。在 AIM 1，我们将充分表征CCN3在副血流调节中的作用。 AIM 2是设计的 to elucidate the mechanisms by which CCN3 deficiency leads to compromised neovascularization and 附带血流。最后，在AIM 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以及其促进新生血管形成能力的基础机制功能性附带血流。