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EGR-1 Mediated Revascularization and Arteriogenic Bypass

EGR-1介导的血运重建和动脉搭桥

基本信息

批准号：
8402621
负责人：
Todd K Rosengart
金额：
$ 31.81万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8402621
关键词：
Acute Address Adenoviruses Anatomy Animals Area Arterial Fatty Streak Binding Biological Biological Assay Biology Blood Vessels Blood capillaries Brain Hypoxia-Ischemia Bromodeoxyuridine Bypass CD44 gene Cell Adhesion Molecules Cells Chronic Clinical Data Clinical Research Clinical Trials Coronary Coronary heart disease Coupling Dependovirus Development Effectiveness Electric Capacitance Family suidae Fibroblast Growth Factor 2 Gene Transfer Generations Genes Growth Growth Factor Harvest Health Home environment Hypoxia In Vitro Individual Inflammation Mediators Inflammatory Intercellular adhesion molecule 1 Intervention Ischemia Knock-in Mouse Knock-out Knockout Mice Label LacZ Genes Ligation Limb structure Mechanical Stress Mediating Mediator of activation protein Modeling Molecular Monocyte Chemoattractant Protein-1 Myocardial Ischemia Obstruction Pathway interactions Perfusion Peripheral Peripheral Vascular Diseases Physiological Platelet-Derived Growth Factor Pneumonectomy Prevention Process Rattus Regulation Relative (related person)Reperfusion Therapy Role Series Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Staining method Stains Stem cells Stimulus Stress Testing Therapeutic Time Tissues Transfection Transforming Growth Factors Transgenes Translating Up-Regulation Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascularization Wild Type Mouse advanced disease angiogenesis arteriole base capillary catalyst cell type conventional therapy cytokine gene transfer vector in vivo macrophage migration monocyte mutant neovascularization neovasculature new growth pre-clinical promoter receptor response sensor shear stress therapeutic angiogenesis transcription factor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Arteriogenesis describes the process of collateral vessel growth that is thought to be a critical biologic response to vascular occlusion. While clinical trials employing the "therapeutic" administration of angiogenic growth factors have generally yielded disappointing results, it now appears that arteriogenesis may be more relevant than angiogenesis in creating a robust, large capacitance, stable neovasculature that can literally provide native "bypasses" of vascular obstructions. In this regard, while ischemia/hypoxia are likely the primary physiologic triggers of angiogenesis, monocyte recruitment in response to vascular shear and other stresses has been implicated as a key early mediator of arteriogenesis. The molecular basis of this activation pathway is unclear, however, and while the arbitrary administration of growth factors may deleteriously bypass "upstream" signaling pathways, an "arteriogenic" transcription factor has yet to be identified. The EGR-1 transcription factor is responsive to changes in shear stress independent of the presence of hypoxia, and can activate a portfolio of potentially arteriogenic growth factors and molecules. In this context, we became intrigued by our demonstration of the rapid upregulation of EGR-1 expression following vascular occlusion, the near- absence of monocyte recruitment and reperfusion following vascular ligation in EGR-1 null mice, and the near-normalization of perfusion following EGR-1 administration to ligated wild type animals. We consequently speculated that EGR-1 is the "missing" signal that transponds the physiologic sequelae of vascular occlusion into an (arteriogenic) neovascularization response. The current aims are therefore to test the hypotheses that EGR-1: 1) induces arteriogenesis as a critical response to vascular occlusion, by upregulation of key arteriogenic mediators, 2) induces monocyte recruitment as the catalyst for this response (and augment this process therapeutically), and 3) can "therapeutically" induce stable revascularization greater than that induced by "downstream" angiogenic mediators. To pursue these aims, we will use vascularization, perfusion and expression assays following vascular ligation in wild type vs. EGR-1 deficient (EGR-knockout or LacZ knock-in) mouse, rat and in a hypercholesterolemic swine myocardial ischemia models with or without VEGF, MCP-1 or EGR-1 administration, via acute or chronic (regulatable and tissue specific) gene transfer vectors. These studies should elucidate the microanatomic site and the locus in molecular signaling pathways of EGR-1 mediated regulation of revascularization, and provide pre-clinical data regarding the benefits of revascularization strategies via arteriogenic vs. angiogenic agents, and via a "master switch" transcription factor vs. downstream mediators.

描述（由申请人提供）：动脉生成描述了侧支血管生长的过程，这被认为是血管闭塞的关键生物学反应。虽然采用血管生成生长因子的“治疗性”给药的临床试验通常产生令人失望的结果，但现在看来，动脉生成可能比血管生成更相关，以产生坚固的、大容量的、稳定的新血管系统，其可以确实地提供血管阻塞的天然“旁路”。在这方面，虽然缺血/缺氧可能是血管生成的主要生理触发因素，但响应于血管剪切和其他应激的单核细胞募集已被认为是动脉生成的关键早期介质。然而，这种激活途径的分子基础尚不清楚，尽管任意施用生长因子可能会有害地绕过“上游”信号传导途径，但“动脉生成”转录因子尚未被鉴定。EGR-1转录因子对剪切应力的变化有反应，与缺氧的存在无关，并且可以激活一系列潜在的动脉生长因子和分子。在这种情况下，我们对以下事实产生了兴趣：我们证明了血管闭塞后EGR-1表达的快速上调，EGR-1缺失小鼠中血管结扎后几乎不存在单核细胞募集和再灌注，以及EGR-1施用至结扎的野生型动物后灌注几乎正常化。因此，我们推测EGR-1是“缺失”的信号，其将血管闭塞的生理后遗症转变为（动脉源性）新血管形成反应。因此，目前的目的是测试以下假设：EGR-1：1）通过上调关键动脉生成介质诱导动脉生成作为对血管闭塞的关键反应，2）诱导单核细胞募集作为该反应的催化剂（并在治疗上增强该过程），和3）可以“治疗性地”诱导稳定的再血管化，其大于由“下游”血管生成介质诱导的再血管化。为了实现这些目标，我们将在野生型与EGR-1缺陷（EGR敲除或LacZ敲入）小鼠、大鼠和高胆固醇血症猪心肌缺血模型中使用血管结扎后的血管形成、灌注和表达测定，通过急性或慢性（可调节和组织特异性）基因转移载体给予或不给予VEGF、MCP-1或EGR-1。这些研究应该阐明EGR-1介导的血管再生调节的分子信号通路中的微解剖部位和位点，并提供关于血管再生策略通过动脉生成剂与血管生成剂以及通过“主开关”转录因子与下游介质的益处的临床前数据。