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

基本信息

批准号：
8627196
负责人：
Aloke Virmani Finn
金额：
$ 37.25万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/8627196
关键词：
5&apos -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 Peroxisome Proliferator-Activated Receptors 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

项目摘要

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.)

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接受最佳医疗疗法和基于介入的导管的管理，但这样做使患者暴露于新的且知之甚少的风险。 PCI和医疗疗法的重大进步在渴望使用新的医疗设备（例如药物洗脱支架（DES））结合糖尿病疗法（例如PPAR3激动剂）（一方面）的渴望之间造成了严重的脱节，一方面是对它们的潜在的不同治疗签名的理解。我们的初步数据表明，由于全身疗法与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粘膜，并可能有助于解释接受DES的糖尿病患者看到的血栓形成并发症的风险增加。）在临床实践中使用的大多数DES旨在洗脱抑制雷帕霉素哺乳动物靶标（MTOR）的药理学剂，雷帕霉素（MTOR）是磷脂酰肌醇激酶与Ser/Thr激酶的磷脂酰肌醇激酶家族的成员。尽管动物研究提到了以下事实：MTOR延迟内皮细胞生长和恢复的抑制剂，但精确的机制尚待调和。从药物开发的角度来看，在存在mTOR抑制剂的情况下，对常用抗糖尿病药物（例如PPAR3激动剂）的功能属性的缺乏了解可能更为关键。该提案的核心目的是通过描述MTOR抑制延迟内皮重生的细胞机制，以更好地理解糖尿病患者患有冠状动脉疾病的治疗策略所需的细胞机制，从而探索MTOR和PPAR3之间的关系和确定这种偶然性的影响和影响的偶然性效果的分子基础，并确定了偶然的病理学影响。再生。更清楚地定义了MTOR在支架放置后的作用以及其与常用糖尿病药物的分子靶标的确切关系可能有助于避免临床情况，从而进一步损害因洗脱药物与全身药物之间的分子相互作用而进一步损害分子相互作用的支架愈合。在该提案中，我们在相关的动脉愈合动物模型中证明了这种类型的相互作用可能会对西罗莫司洗脱支架位置后，由于PPAR3激动剂与MTOR抑制剂Sirolimus之间的分子相互作用而导致的支架位置。我们提出的研究将使我们能够1）定义动脉壁MTOR抑制与糖尿病兔模型中支架重新皮层化相结合的动脉壁抑制作用； 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。）

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Making Novel Genetic Associations With Carotid Intima-Media Thickness Using the UK Biobank.

利用英国生物库建立颈动脉内膜中层厚度的新遗传关联。

DOI：
10.1161/atvbaha.119.313784
发表时间：
2020
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Guo,Liang;Cornelissen,Anne;Sakamoto,Atsushi;Finn,AlokeV
通讯作者：
Finn,AlokeV

Metformin impairs endothelialization after placement of newer generation drug eluting stents.

放置新一代药物洗脱支架后，二甲双胍会损害内皮化。

DOI：
10.1016/j.atherosclerosis.2013.06.001
发表时间：
2013
期刊：
Atherosclerosis
影响因子：
5.3
作者：
Habib,Anwer;Karmali,Vinit;Polavarapu,Rohini;Akahori,Hirokuni;Pachura,Kim;Finn,AlokeV
通讯作者：
Finn,AlokeV

Do animal models of vein graft atherosclerosis predict outcomes in man?

静脉移植动脉粥样硬化的动物模型可以预测人类的结果吗？

DOI：
10.1016/j.atherosclerosis.2012.04.028
发表时间：
2012
期刊：
Atherosclerosis
影响因子：
5.3
作者：
Yazdani,SaamiK;Otsuka,Fumiyuki;Nakano,Masataka;Finn,AlokeV;Virmani,Renu
通讯作者：
Virmani,Renu

The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents.

DOI：
10.1016/j.jacc.2011.01.011
发表时间：
2011-03-15
期刊：
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
影响因子：
24
作者：
Nakazawa, Gaku;Otsuka, Fumiyuki;Nakano, Masataka;Vorpahl, Marc;Yazdani, Saami K.;Ladich, Elena;Kolodgie, Frank D.;Finn, Aloke V.;Virmani, Renu
通讯作者：
Virmani, Renu

Everolimus-eluting stents improve vascular response in a diabetic animal model.

DOI：
10.1161/circinterventions.113.001023
发表时间：
2014-08
期刊：
Circulation. Cardiovascular interventions
影响因子：
0
作者：
Habib A;Karmali V;John MC;Polavarapu R;Nakazawa G;Pachura K;Davis T;Kolodgie FD;Virmani R;Finn AV
通讯作者：
Finn AV