mTOR Signaling and Vascular Repair in an Experimental Model of Diabetes Mellitus

描述(申请人提供)：旨在减少糖尿病患者不良心脏事件的治疗策略包括最佳药物治疗和基于介入性导管的管理，但这样做会使患者面临新的和鲜为人知的风险。在经皮冠状动脉介入治疗和医疗治疗方面的重大进展一方面造成了急于使用药物洗脱支架(DES)等新型医疗设备与糖尿病治疗(如PPAR3激动剂)相结合的渴望，另一方面也造成了对它们潜在的不同治疗信号可能如何在临床上相互作用的理解之间的严重脱节。我们的初步数据表明，由于全身治疗和局部洗脱药物之间的分子相互作用，这些治疗组合可能会损害支架的再内皮化，并可能有助于解释接受DES治疗的糖尿病患者血栓并发症风险增加的原因。)临床上使用的大多数DES都是为了洗脱药物，如西罗莫司，它抑制哺乳动物靶标雷帕霉素(MTOR)，mTOR是磷脂酰肌醇激酶相关的丝氨酸/苏氨酸激酶家族的成员。虽然动物研究暗示mTOR的抑制剂可以延缓内皮细胞的生长和恢复，但其确切的机制尚不清楚。从药物开发的角度来看，对常用抗糖尿病药物如PPAR3激动剂在存在mTOR抑制剂的情况下功能属性的相关缺乏了解可能更为关键。这项建议的中心目的是通过描绘mTOR抑制延缓内皮再生的细胞机制，探索mTOR和PPAR3之间关系的分子基础，并确定这种相互作用对血管内皮生长因子表达和内皮再生的影响，从而更好地了解糖尿病合并冠心病患者制定治疗策略所需的细胞机制。更清楚地了解mTOR在支架置入后内皮恢复中的作用，以及它与常用糖尿病药物分子靶点的精确关系，可能有助于避免由于洗脱药物和全身药物之间的分子相互作用而进一步损害支架愈合的临床情况。在这项建议中，我们在相关的动脉愈合动物模型中证明，由于PPAR3激动剂和mTOR抑制剂西罗莫司之间的分子相互作用，这种类型的相互作用可以对放置西罗莫司洗脱支架后的内皮化产生显著影响。我们提出的研究将使我们能够1)确定动脉壁mTOR抑制与PPAR3激动剂联合使用对糖尿病兔模型支架再内皮化的影响；2)阐明mTOR与PPAR3相互作用的相关分子机制以及最终对血管内皮生长因子表达的病理生理影响；3)阐明mTOR抑制剂延缓支架愈合的确切机制。) 公共卫生相关性：旨在减少糖尿病患者不良心脏事件的治疗策略包括最佳药物治疗和基于介入性导管的管理，但这样做会使患者面临新的和鲜为人知的风险。血运重建技术和医疗治疗的重大进步一方面造成了对使用药物洗脱支架(DES)等新医疗设备与糖尿病治疗相结合的渴望与对其潜在的不同治疗特征如何临床相互作用的理解之间的严重脱节。更好地了解这种关系将改善糖尿病和冠状动脉疾病患者的治疗结果。

DESCRIPTION (provided by applicant): Treatment strategies aimed at reducing adverse cardiac events in patients with diabetes have embraced both optimal medical therapy and interventional catheter based management but in doing so have exposed patients to new and poorly understood risks. Major advances in PCI and medical therapies have created a serious disconnect between the eagerness to use new medical devices such as drug eluting stents (DES) in combination with diabetic therapies such as PPAR3 agonists on the one hand and the understanding of how their underlying divergent therapeutic signatures might clinically interact on the other. Our preliminary data suggest that these treatment combinations may impair stent re-endothelialization due to molecular interactions between systemic therapies and locally eluted drug and may help to explain the increased risk of thrombotic complications seen in patients with diabetes receiving DES. ) The majority of DES using in clinical practice are designed to elute pharmacologic agents such as sirolimus that inhibit the mammalian target of rapamycin (mTOR), a member of the phosphatidylinositol kinase-related family of Ser/Thr kinase. Although animal studies have alluded to the fact that inhibitors of mTOR delay endothelial cell growth and recovery, the precise mechanisms are yet to be reconciled. The related lack of understanding of the functional attributes of commonly used anti-diabetic agents such as PPAR3 agonist in the presence of mTOR inhibitors is perhaps more critical from the standpoint of drug development. The central purpose of this proposal is to provide a better understanding of the cellular mechanisms required to inform treatment strategies in diabetic patients with coronary disease by delineating the cellular mechanisms by which mTOR inhibition delays endothelial regrowth, exploring the molecular basis for the relationship between mTOR and PPAR3, and determining the potential pathophysiological consequences and impact of this interaction on expression of VEGF and endothelial regrowth. More clearly defining the role of mTOR in endothelial recovery after stent placement as well as its precise relationship to the molecular targets of commonly used diabetes medications may help avoid clinical situations that further impair stent healing due to molecular interactions between eluted drug and systemic medications. In this proposal, we demonstrate in a relevant animal model of arterial healing that this type of interaction can have a significant impact on endothelialization after sirolimus eluting stent placement due to molecular interactions between PPAR3 agonists and the mTOR inhibitor sirolimus. The studies we propose will enable us 1) to define the impact of arterial wall mTOR inhibition in combination with PPAR3 agonists on stent re- endothelialization in a diabetic rabbit model; 2) elucidate the relevant molecular mechanisms of mTOR to PPAR3 interactions and the ultimate pathophysiological impact on VEGF expression; and 3) delineate the exact mechanisms by which mTOR inhibitors delay stent healing.) PUBLIC HEALTH RELEVANCE: Treatment strategies aimed at reducing adverse cardiac events in patients with diabetes mellitus have embraced both optimal medical therapy and interventional catheter based management but in doing so have exposed patients to new and poorly understood risks. Major advances in revascularization techniques and medical therapies have created a serious disconnect between the eagerness to use new medical devices such as drug eluting stents (DES) in combination with diabetic therapies on the one hand and the understanding of how their underlying divergent therapeutic signatures might clinically interact on the other. A better understanding of this relationship will improve treatment outcomes for patients with diabetes mellitus and coronary artery disease.