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Role of Notch Signaling in atherosclerosis and Stem Cell Mediated Arterial Repair

Notch 信号传导在动脉粥样硬化和干细胞介导的动脉修复中的作用

基本信息

批准号：
9211368
负责人：
Omaida C Velazquez
金额：
$ 53.76万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211368
关键词：
Adherence Aging Alpha Cell American Aorta Aortic Diseases Apolipoprotein E Area Arterial Fatty Streak Arterial Injury Arterial Occlusive Diseases Atherosclerosis Binding Biological Blood Vessels Bone Marrow Bone Marrow Cells CD34 gene Cause of Death Cell Adhesion Molecules Cell Aging Cell Communication Cell Lineage Cell surface Cells Chronic Coronary Arteriosclerosis Dendrimers Development Disease Progression E-Selectin Effectiveness Endothelial Cells Endothelium Equilibrium Genes Genetically Engineered Mouse Glues High Fat Diet Homeostasis Hyperlipidemia Hypertension In Vitro Inflammation Inflammatory Inflammatory Response Injury Intercellular adhesion molecule 1 Intravenous Intravenous infusion procedures KDR gene Knowledge Label Lesion Leukocytes Ligands Link Maintenance Mechanics Mediating Methods Mus Partner in relationship Pathogenesis Pathway interactions Patients Peptides Peripheral arterial disease Phenotype Play Prevention approach Process Recruitment Activity Research Risk Factors Role Rupture Safety Signal Pathway Signal Transduction Smoking Stem cells System Technology Therapeutic United States Wit Work aged base cadherin 5 cell type cerebrovascular chemokine clinically relevant cytokine design genetic manipulation healing human data in vivo injured injury and repair innovation loss of function mortality mouse model nanoparticle notch protein novel novel strategies paracrine plaque lesion prevent progenitor public health relevance receptor repaired senescence stem cell biology surface coating vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis and its associated complications are the leading cause of death in the United States. Atherosclerosis results from inflammation followed by dysregulation of arterial homeostasis that hinges on the balance between arterial injury and arterial repair. Arterial injury induced by risk factors such as hypertension, hyperlipidemia, smoking and aging results in vascular inflammation and endothelial cell (EC) senescence. During inflammation, activated endothelium produces pro-inflammatory cytokines/chemokines and cell adhesion molecules that recruit circulating leukocytes to the developing arterial plaque. Meanwhile, 'repair cells' are recruited to areas of injury and stave of the development of atherosclerosis. The main action of these repair cells may replace the injured EC and/or secrete paracrine factors. When successful, these reparative processes halt the inflammatory process, preventing further damage. However, chronic arterial injury may overwhelm the ability of repair cells to maintain arterial homeostasis. Thus, atherosclerotic lesions likely begin to form as arterial repair fails, rather than merely following arterial injury Although the specific cell types that repair the arterial wall have not yet been defined, experimental data from human patients suggests that Lin- bone marrow-derived cells (Lin- BMC) may be important for repair. We herein refer to these cells as repair competent bone marrow cells (RC- BMC). We have recently found that Notch signaling activity is differentially regulated in the EC lining the arterial plaque (in which a "higher" Notch activity is connected wit vascular inflammation and EC senescence). We also found that bone marrow progenitor/stem cells show progressively "lower" Notch activity as the arterial plaques progress. We hypothesize that alteration of Notch signaling regulates development/progression of atherosclerosis and modulates function of putative RC-BMC thus altering their ability to maintain arterial homeostasis. Our specific working hypothesis is that there exists a functional or causal relationship between high activity of Notch signaling and increasing atherosclerosis burden. Our testable 'proof-of-principle' hypothesis is that Notch signaling determines phenotype associated with arterial damage as well as repair capacity of BMC (RC Vs. RI). We propose to delineate the functional impact of Notch signaling on atherosclerosis development/progression and of alteration of Notch signaling activity (in Lin- BMC) on atherosclerosis plaque burden and plaque repair after disruption. We will also develop a clinically-relevant method for atherosclerotic lesion-specific cell delivery via an innovative nanoparticle-mediated technology. This work will exponentially advance knowledge on the pathogenesis of atherosclerosis and the role of progenitor/stem-cell-mediated arterial repair. Ultimately, the research may result in a paradigm-shifting therapeutic approach to the prevention and treatment of atherosclerosis.

描述（由申请人提供）：动脉粥样硬化及其相关并发症是美国的主要死亡原因。动脉粥样硬化是由炎症引起的，随后是动脉稳态失调，这取决于动脉损伤和动脉修复之间的平衡。高血压、高脂血症、吸烟和衰老等危险因素引起的动脉损伤导致血管炎症和内皮细胞（EC）衰老。在炎症过程中，活化的内皮细胞产生促炎细胞因子/趋化因子和细胞粘附分子，其将循环白细胞募集到发展中的动脉斑块。与此同时，“修复细胞”被招募到损伤区域，延缓动脉粥样硬化的发展。这些修复细胞的主要作用可能是替代受损的EC和/或分泌旁分泌因子。当成功时，这些修复过程停止炎症过程，防止进一步的损伤。然而，慢性动脉损伤可能压倒修复细胞维持动脉稳态的能力。因此，动脉粥样硬化病变可能开始形成为动脉修复失败，而不是仅仅在动脉损伤后。尽管修复动脉壁的特定细胞类型尚未确定，但来自人类患者的实验数据表明Lin-骨髓来源的细胞（Lin-BMC）可能对修复很重要。我们在此将这些细胞称为有修复能力的骨髓细胞（RC-BMC）。我们最近发现Notch信号传导活性在动脉斑块内衬的EC中受到差异调节（其中“较高”Notch活性与血管炎症和EC衰老有关）。我们还发现，随着动脉斑块的进展，骨髓祖细胞/干细胞显示出逐渐“降低”的Notch活性。我们假设Notch信号的改变调节动脉粥样硬化的发展/进展，并调节推定的RC-BMC的功能，从而改变其维持动脉稳态的能力。我们具体的工作假设是，Notch信号的高活性和动脉粥样硬化负荷增加之间存在功能或因果关系。我们可检验的“原理证明”假设是Notch信号传导决定与动脉损伤相关的表型以及BMC的修复能力（RC与RI）。我们建议描述Notch信号传导对动脉粥样硬化发展/进展的功能影响，以及Notch信号传导活性（在Lin-BMC中）的改变对动脉粥样硬化斑块负荷和破坏后斑块修复的功能影响。我们还将开发一种临床相关的方法，通过创新的纳米粒子介导的技术，动脉粥样硬化病变特异性细胞输送。这项工作将指数推进动脉粥样硬化的发病机制和祖细胞/干细胞介导的动脉修复的作用的知识。最终，这项研究可能会导致一种范式转变的治疗方法，以预防和治疗动脉粥样硬化。