2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645257摘要：代謝症候群（Metabolic syndrome，MetS)，其臨床表現包括腹部肥胖、胰島素阻抗、高血壓和血脂異常，與冠狀動脈疾病（coronary artery disease，CAD)的風險增加有關。根據2005至2008年間進行的全國健康調查顯示，約20%的台灣人患有MetS ;其盛行率隨著年齡的增長而增加，65歲以上年齡層的患者超過40%。内臟性肥胖在MetS的發展過程中扮演一個中心的角色。内臟脂肪組織分泌促炎細胞因子(proinflammatory cytokines)導致低度的全身性發炎，促使動脈產生粥狀硬化（atherosclerosis)。MetS合併CAD已成為一個主要的健康問題。儘管經皮冠狀動脈介入治療（percutaneous coronaryintervention, PCI)可有效的治療冠心病，新内膜增生（neointimal hyperplasia)和隨後的再狹窄(restenosis)仍然是主要的限制。與MetS相關的再狹窄致病機轉中，脂肪細胞釋放的發炎因子扮演了重要作用。因此，針對MetS致病機制的抗炎治療（anti-inflammation therapy)策略，有其迫切性。骨鑛間葉幹細胞（bone marrow-derived mesenchymal stem cells, BMSCs)對調節發炎反應具有 相當的治療價值。BMSCs可藉由產生調節性T細胞（regulatory T cell)或免疫抑制因子，如前列腺 素E2 (prostaglandin E2)、IL-10和TGF- P，抑制免疫反應。雖然將BMSCs用於抗發炎治療極具潛 力，但MetS患者是否可用自體(autologous) BMSCs進行治療則仍有疑問。MetS可導致大鼠骨髓内 皮前驅細胞（endothelial progenitor cell)的功能受損而減少其血管新生（angiogenesis)能力。肥胖 或MetS受試者的脂肪幹細胞具有較低的增殖能力及血管新生和硬骨發生（osteogenesis)的潛能。 MetS對BMSCs免疫調節功能的影響尚不清楚。我們推測，MetS受試者體内的慢性發炎環境可能會 影響BMSCs的免疫抑制特性，因此限制了 MetS患者使用自體的BMSCs做治療。本計晝中，我們將建立MetS的豬隻模型，研究MetS對BMSCs免疫調節功能的影響。在第 一年中，我們將（1)評估分離自MetS發展過程中不同時間點的BMSCs之免疫調節效力；（2)比 較正常及MetS BMSCs分泌的免疫抑制細胞因子表達譜（expression profile)，從而找出MetS BMSCs 缺乏的免疫抑制關鍵因子，以及（3)確認補充這些關鍵因子是否可還原MetS BMSCs的免疫調節功 能。在第二年中，我們將建立一個MetS合併動脈粥樣硬化的豬隻模型（4)比較正常BMSCs、MetS BMSCs、以及MetS BMSCs合併關鍵免疫抑制分子三者防止支架内再狹窄的能力。此研究結果將有 助於釐清使用自體BMSCs治療MetS患者動脈粥樣硬化的可能性。<br> Abstract: Metabolic syndrome (MetS), characterized by a variety of clinical manifestations including abdominal obesity, insulin resistance, hypertension, and dyslipidemia, is associated with an increased risk of coronary artery disease (CAD). According to a national health survey performed between 2005 and 2008, approximately 20% Taiwanese has metabolic syndrome. The prevalence of people with metabolic syndrome increases with age, affecting more than 40 percent of people above 65.Visceral obesity playing a central role in the development of metabolic syndrome. The production of proinflammatory cytokines in visceral adipose tissue tends to induce a low-level systemic inflammation that contributes to atherosclerosis. MetS patients with CAD have become a major health issue. Although percutaneous coronary intervention is effective to treat CAD, the neointimal hyperplasia and the subsequent restenosis remains the major limitation. In the pathogenesis of MetS-associated re-stenosis, the release of inflammatory adipocytokines is known to play an important role. Accordingly, anti-inflammation therapy, a strategy targeting the pathogenic mechanism of MetS, is mandatory.Mesenchymal stem cells (MSCs) offer considerable therapeutic value in modulating inflammation. MSCs have the ability to suppress immune reactions via regulatory T cells and producing immune suppressive factors such as, prostaglandin E2 and IL-10, and TGF-P. While the anti-inflammatory properties are promising, the application of MSCs in MetS subjects is still questionable. In MetS rats, BM-derived EPCs develop marked functional impairment, resulting in severely reduced angiogenic capacity. Adipose tissue-derived MSCs from obese or MetS subjects display reduced proliferative, angiogenic, and osteogenic potential. The effects of MetS on MSC-mediated immunomodulation is not clear. We speculate that the chronic inflammatory environment in MetS subjects may affect the immunosuppressive properties of MSCs and limit the use of MSC therapy in MetS patients.In this study, we propose to investigate the influence of MetS on the immunomodulatory potential ofBMSCs in pig models of MetS. In the first year we will: (1) evaluate the immunosuppressive potency of BMSCs isolated at different time points in the development of MetS; (2) analyze the expression profiles of immunosuppressive cytokines secreted by normal and MetS BMSCs and thus to identify the key factors that contribute to BMSC dysfunction in MetS; and (3) confirm the importance of the key factors by their potential to reconstitute the immunomodulatory potency of MetS BMSCs. In the second year, we will establish an experimental arteriosclerosis model in MetS pigs. (4) The ability of normal and MetS BMSCs, as well as the combination of MetS BMSCs with candidate immunosuppressive molecules to prevent in-stent restenosis will be compared. The results will be helpful to clarify the possibility of autologous MSC therapy in patients with MetS-associated atherosclerotic diseases.代謝症候群骨髓間葉幹細胞抗發炎動脈粥樣硬化metabolic syndromemesenchymal stem cellanti -inflammationatherosclerosis