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

描述(申请人提供)：动脉粥样硬化及其相关并发症是美国主要的死亡原因。动脉粥样硬化是由炎症引起的，继而是取决于动脉损伤和动脉修复之间的平衡的动脉内稳态失调。高血压、高脂血症、吸烟和衰老等危险因素导致动脉损伤，导致血管炎症和内皮细胞(EC)衰老。在炎症过程中，激活的内皮细胞产生促炎细胞因子/趋化因子和细胞黏附分子，将循环中的白细胞招募到正在形成的动脉斑块中。与此同时，“修复细胞”被招募到动脉粥样硬化的损伤和延缓发展的区域。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，这些修复过程就会停止炎症过程，防止进一步的损害。然而，慢性动脉损伤可能会压倒修复细胞维持动脉内稳态的能力。因此，动脉粥样硬化病变可能随着动脉修复失败而开始形成，而不是仅仅在动脉损伤后形成。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-BMC可能在修复中起重要作用。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信号活性在动脉斑块衬里的EC中受到不同程度的调节(在这种情况下，Notch活性“较高”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生和发展，并调节可能的RC-BMC的功能，从而改变其维持动脉内稳态的能力。我们的具体工作假设是，Notch信号的高活性与动脉粥样硬化负担的增加之间存在功能或因果关系。我们的可测试的“原则证明”假说是，Notch信号决定了与动脉损伤相关的表型以及BMC的修复能力(Rcv.国际扶轮)。我们建议描述Notch信号在动脉粥样硬化发生发展中的功能影响，以及Notch信号活性的改变(在LIN-BMC中)对动脉粥样硬化斑块负荷和斑块中断后的修复的影响。我们还将开发一种临床相关的方法，通过创新的纳米颗粒介导性技术传递动脉粥样硬化病变特异性细胞。这项工作将成倍地提高对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认识。最终，这项研究可能会导致一种预防和治疗动脉粥样硬化的范式转变的治疗方法。

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.