P1: Vascular Endothelial Cells Recruitment, RA Synovium, Chemotaxis Angiogenesis

P1：血管内皮细胞募集、RA 滑膜、趋化性血管生成

• 批准号: 7483077
• 负责人: JEFFREY HAROLD RUTH
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483077
• 关键词: Adoptive Transfer; Animal Model; Apoptosis; Apoptotic; Area; Arthritis; Blood Vessels; CD34 gene; Cell Adhesion Molecules; Cell Differentiation process; Cell physiology; Cells; Characteristics; Chemotaxis; Chimera organism; Chronic; Commit; Dermal; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Evaluation; Event; Growth; Homing; Human; Immigration; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Joints; Mediating; Methods; Modeling; Personal Satisfaction; Play; Process; Recruitment Activity; Relative (related person); Research; Research Design; Rheumatoid Arthritis; Rodent Model; Role; SCID Mice; Series; Site; Stem cells; Synovial Membrane; Testing; Therapeutic; Tissues; Umbilical Cord Blood; Undifferentiated; Vascular Endothelial Cell; angiogenesis; arthropathies; cell motility; cell type; chemokine; in vivo; insight; matrigel; neovascularization; precursor cell; tool; vasculogenesis

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with microvascular expansion in synovium as a characteristic feature of disease progression. Synovial neovascularization requires either proliferation of existent vascular endothelial cells (ECs), or recruitment from endothelial precursor cells (EPCs) differentiating into ECs. EC recruitment and differentiation are orchestrated by a series of events including vessel lumen expression of adhesion molecules that capture circulating EPCs, followed by differentiation into mature ECs. Chemokines are certainly involved in this process, and it has been suggested that chemokines may play a role in angiogenesis by inhibiting EC apoptosis, decreasing EC turnover and favoring vessel growth. This would result in increased cell recruitment to the RA joint and exacerbate inflammatory responses. Therefore, understanding EC recruitment and apoptosis are critical for development of therapeutics to combat RA. It is well established that EPCs differentiate into various mature cell types, whereas differentiated ECs can be derived from other progenitor cells. However, it is unclear how and when EPCs differentiate into different cells in vivo. Thus, looking at non-committed stem cells poses problems when studying their role in neovascularization and angiogenesis in vivo. In addition, little information exists regarding the relative contribution of differentiated or undifferentiated ECs to synovial neovascularization that occurs in RA. This study will clarify how ECs are recruited to RA synovium and will determine to what extent chemokines mediate this process and enhance vessel growth. We propose to investigate the hypothesis that differentiated dermal human microvascular endothelial cells (HMVECs), as well as undifferentiated ECs are similarly recruited to sites of neovascularization in the RA synovium, wherein they incorporate into the vascular wall as functional endothelium. Specifically, we will compare differentiated and undifferentiated EC recruitment to normal (NL) and RA synovial tissue (ST) engrafted in a severe combined immunodeficient (SCID) mouse chimera. With this model, we will investigate the chemokines that mediate EC recruitment, initiate vessel formation, and mediate EC anti-apoptotic activity in vivo. Overall, the results of this study will provide a relatively simple method to examine EC recruitment in vivo, and provide a suitable alternative to investigate angiogenesis, EC chemotaxis, and apoptosis in a relevant animal model of RA.

类风湿关节炎(RA)是一种滑膜微血管扩张的慢性炎症性关节疾病 作为疾病进展的一个特征。滑膜新生血管需要要么增殖 存在的血管内皮细胞(ECs)，或从内皮前体细胞(EPC)招募 分化为ECs。EC招聘和差异化由一系列活动协调，包括 捕获循环内皮祖细胞的黏附分子在血管腔中的表达，随后分化为 成熟的欧洲议会议员。趋化因子当然参与了这一过程，而且有人认为趋化因子 可能通过抑制内皮细胞凋亡、降低内皮细胞周转和促进血管生成而发挥血管生成作用。 成长。这将导致RA关节的细胞募集增加，并加剧炎症 回应。因此，了解EC募集和细胞凋亡对于肿瘤的发展至关重要。 对抗类风湿性关节炎的治疗。众所周知，内皮祖细胞分化为各种成熟细胞类型， 而分化的内皮细胞可以从其他祖细胞分化而来。然而，目前还不清楚如何以及何时进行 在体内，内皮祖细胞分化为不同的细胞。因此，观察未被承诺的干细胞会带来问题。 当研究它们在体内新生血管和血管生成中的作用时。此外，几乎没有信息存在。 关于分化或未分化的内皮细胞对滑膜新生血管的相对贡献 发生于类风湿关节炎。这项研究将阐明内皮细胞是如何被招募到RA滑膜中的，并将确定在多大程度上 趋化因子调节这一过程，促进血管生长。我们建议对这一假设进行调查 分化的真皮人微血管内皮细胞(HMVECs)以及未分化的ECs 类似地被招募到RA滑膜中的新生血管部位，在那里它们结合到 血管壁作为功能性内皮细胞。具体地说，我们将比较差异化和未差异化的EC 严重联合免疫缺陷患者植入正常滑膜组织(NL)和RA滑膜组织(ST) (SCID)小鼠嵌合体。通过这个模型，我们将研究介导EC招募的趋化因子， 在体内启动血管形成，并介导EC抗细胞凋亡的活性。总体而言，这项研究的结果将 提供了一种相对简单的方法来检查EC在体内的招募，并提供了一种合适的替代方法 在相关的类风湿关节炎动物模型中研究血管生成、EC趋化和细胞凋亡。