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

描述（由申请人提供）：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导管的管理，但这样做会使患者暴露于新的和知之甚少的风险。PCI和医学治疗的重大进展已经造成了一方面渴望使用新的医疗器械（如药物洗脱支架（DES））与糖尿病治疗（如PPAR 3激动剂）联合使用，另一方面理解其潜在的不同治疗特征如何在临床上相互作用之间的严重脱节。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再内皮化，并可能有助于解释接受DES的糖尿病患者血栓并发症风险增加的原因。在临床实践中使用的大多数DES被设计为抑制药物如西罗莫司，其抑制雷帕霉素（mTOR）的哺乳动物靶标，其是丝氨酸/苏氨酸激酶的磷脂酰肌醇激酶相关家族的成员。尽管动物研究已经暗示了mTOR抑制剂延迟内皮细胞生长和恢复的事实，但确切的机制尚未得到协调。从药物开发的角度来看，对常用抗糖尿病药物（如在mTOR抑制剂存在下的PPAR 3激动剂）的功能属性的相关缺乏了解可能更为关键。该提案的中心目的是通过描绘mTOR抑制延迟内皮再生的细胞机制，探索mTOR和PPAR 3之间关系的分子基础，并确定这种相互作用对VEGF表达和内皮再生的潜在病理生理学后果和影响。更清楚地定义mTOR在支架置入后内皮恢复中的作用以及其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。在该提案中，我们在动脉愈合的相关动物模型中证明，由于PPAR 3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西罗莫司洗脱支架置入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）在糖尿病兔模型中确定动脉壁mTOR抑制联合PPAR 3激动剂对支架再内皮化的影响; 2）阐明mTOR与PPAR 3相互作用的相关分子机制以及对VEGF表达的最终病理生理学影响; 3）描述mTOR抑制剂延迟支架愈合的确切机制。

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.)