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

糖尿病实验模型中的 mTOR 信号传导和血管修复

• 批准号: 8225220
• 负责人: Aloke Virmani Finn
• 金额: $ 37.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-20 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225220
• 关键词: 5' -AMP-activated protein kinase; 70-kDa Ribosomal Protein S6 Kinases; Address; Affect; Agonist; Animal Model; Animals; Antidiabetic Drugs; Arterial Injury; Behavior; Binding; Binding Proteins; Biological Assay; Blood Vessels; Cardiac; Catheters; Cell Culture System; Cells; Clinical; Complex; Coronary Arteriosclerosis; Coronary heart disease; Critical Pathways; Data; Diabetes Mellitus; Endothelial Cells; Eukaryotic Initiation Factor-4E; Event; Experimental Models; Family; Fibroblast Growth Factor; Genetic Transcription; Growth Factor; Healed; Homeostasis; Human; In Vitro; Injury; Intercellular Junctions; Left; Mediating; Mediator of activation protein; Medical; Medical Device; Metabolic Control; Metabolism; Metals; Metformin; Modeling; Molecular; Molecular Target; New Agents; Nuclear Orphan Receptor; Nuclear Receptors; Oryctolagus cuniculus; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Protein Dephosphorylation; Raptors; Recovery; Regulation; Relative (related person); Ribosomal Proteins; Risk; Role; Signal Transduction; Sirolimus; Stents; Subfamily lentivirinae; Systemic Therapy; Techniques; Therapeutic; Transcription Coactivator; Treatment outcome; Up-Regulation; Vascular Endothelial Growth Factors; base; cell growth; clinical practice; design; diabetic; diabetic patient; drug development; genetic regulatory protein; healing; human FRAP1 protein; hypoxia inducible factor 1; improved; in vivo; inhibitor/antagonist; insulin signaling; mTOR inhibition; mTOR protein; member; migration; novel; prevent; public health relevance; repaired; research study; response; restenosis; rosiglitazone; small hairpin RNA; transcription factor; treatment strategy

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.

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已采用最佳药物治疗和基于介入​​导管的管理，但这样做使患者面临新的且知之甚少的风险。 PCI 和药物疗法的重大进步一方面渴望使用药物洗脱支架 (DES) 等新医疗设备与 PPAR3 激动剂等糖尿病疗法相结合，另一方面又对其潜在的不同治疗方法的理解产生了严重脱节。临床上，签名可能会与另一个签名相互作用。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 的糖尿病患者出现血栓并发症的风险增加。 ) 临床实践中使用的大多数 DES 旨在洗脱抑制哺乳动物雷帕霉素靶点 (mTOR) 的药物，例如西罗莫司，mTOR 是磷脂酰肌醇激酶相关 Ser/Thr 激酶家族的成员。尽管动物研究已经暗示 mTOR 抑制剂会延迟内皮细胞的生长和恢复，但其确切机制尚未得到证实。从药物开发的角度来看，对常用抗糖尿病药物（例如 PPAR3 激动剂）在 mTOR 抑制剂存在下的功能属性缺乏了解可能更为关键。该提案的中心目的是通过描述 mTOR 抑制延迟内皮再生的细胞机制，探索 mTOR 和冠状动脉疾病之间关系的分子基础，从而更好地了解糖尿病合并冠心病患者治疗策略所需的细胞机制。 PPAR3，并确定潜在的病理生理后果以及这种相互作用对 VEGF 表达和内皮再生的影响。更清楚地定义 mTOR 在支架放置后内皮恢复中的作用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。在本提案中，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西罗莫司洗脱支架放置后的内皮化产生重大影响。我们提出的研究将使我们能够 1) 确定动脉壁 mTOR 抑制与 PPAR3 激动剂联合对糖尿病兔模型中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对VEGF表达的最终病理生理影响； 3) 描述 mTOR 抑制剂延迟支架愈合的确切机制。） 公共健康相关性：旨在减少糖尿病患者不良心脏事件的治疗策略已采用最佳药物治疗和基于介入​​导管的管理，但这样做使患者面临新的且知之甚少的风险。血运重建技术和医学疗法的重大进步，一方面渴望使用药物洗脱支架 (DES) 等新医疗设备与糖尿病疗法相结合，另一方面又对其潜在的不同治疗特征如何在临床上发挥作用的理解之间造成了严重脱节。互相影响对方。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。