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

• 批准号: 8828769
• 负责人: Omaida C Velazquez
• 金额: $ 55.16万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828769
• 关键词: Adherence; Aging; American; Aorta; 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 Line; Cell Lineage; Cell surface; Cells; Chronic; Coronary Arteriosclerosis; Dendrimers; Development; Diet; Disease Progression; E-Selectin; Effectiveness; Endothelial Cells; Endothelium; Equilibrium; Fatty acid glycerol esters; Genes; Genetically Engineered Mouse; Glues; Healed; Health; Homeostasis; Hyperlipidemia; Hypertension; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Intravenous infusion procedures; Knowledge; Label; Lesion; Leukocytes; Ligands; Link; Maintenance; 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; Vascular Endothelial Growth Factor Receptor-2; Wit; Work; aged; base; cadherin 5; cell type; cerebrovascular; chemokine; clinically relevant; cytokine; design; feeding; 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; receptor; repaired; response to injury; senescence; stem cell biology; surface coating; vascular inflammation

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死亡的主要原因。动脉粥样硬化是由炎症引起的，随后是动脉内稳态失调，而动脉内稳态的平衡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、衰老等危险因素引起的动脉损伤可导致血管炎症和内皮细胞（EC）衰老。在炎症期间，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，招募循环白细胞到正在形成的动脉斑块。与此同时，“修复细胞”被招募到损伤区域，阻止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。一旦成功，这些修复过程就会阻止炎症过程，防止进一步的损伤。然而，慢性动脉损伤可能会破坏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在动脉修复失败时开始形成，而不仅仅是在动脉损伤之后。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-骨髓源性细胞（Lin- BMC）可能对修复很重要。我们在此将这些细胞称为修复能力骨髓细胞（RC- BMC）。我们最近发现，Notch信号活性在动脉斑块内壁的EC中受到不同的调节（其中“较高”的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/干细胞的Notch活性逐渐“降低”。我们假设Notch信号的改变调节了动脉粥样硬化的发生/进展，并调节了假定的RC-BMC的功能，从而改变了它们维持动脉稳态的能力。我们的具体工作假设是Notch信号高活性与动脉粥样硬化负担增加之间存在功能或因果关系。我们可测试的“原理证明”假设是Notch信号决定与动脉损伤相关的表型以及BMC的修复能力（RC Vs. RI）。我们建议描述Notch信号在动脉粥样硬化发生/进展中的功能影响，以及Notch信号活性（in Lin- BMC）的改变对动脉粥样硬化斑块负荷和斑块破坏后修复的影响。我们还将通过创新的纳米颗粒介导技术开发一种临床相关的动脉粥样硬化病变特异性细胞递送方法。这项工作将以指数方式推进对动脉粥样硬化发病机制和祖细胞/干细胞介导的动脉修复作用的认识。最终，这项研究可能会导致一种范式转换的治疗方法来预防和治疗动脉粥样硬化。