Cardiovascular disease accounts for nearly one third of deaths globally, and Coronary Artery Disease remains the #1 cause of death in the United States. The introduction of the Drug-Eluting Stent (DES) in 2002 revolutionized the field of PCI, by significantly reducing rates of restenosis when compared to bare-metal stents (BMS). Despite the clear clinical advantage of DES, concerns have been raised over their long-term safety, with particular reference to stent thrombosis related to delayed endothelialisation. New therapeutic strategies that can specifically target VSMC and other infiltrated cells but not VEC are needed. MiRNAs act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Recent studies show that the mir-143/145 cluster plays important roles in the phenotypic switching of SMC between the quiescent and the proliferative phenotypes. These findings opened the door to potentially novel therapies for restenosis. However, our preliminary data show that increasing the expression of these miRNAs in a non-targeted manner inhibits VEC growth and migration. Therefore, in this application we propose to: 1) Investigate the effect of a mir-143/145 de-targeting strategy on VSMC and VEC proliferation and migration in vitro. 2) Evaluate the specificity and the sensitivity of the de-targeting strategy in a rat carotid artery balloon injury in vivo, and 3) Examine the mir-143/145 de-targeting strategy in the same balloon injury model in vivo. To achieve these aims we will use the endothelial cell specific miRNA to our advantage (mir-126), and we will insert target sequences for mir-126 or random sequences into the 3'-end of a mir-143/mir-145 expressing lentivirus. Infected VSMC and VEC will be tested for proliferation and migration. The same viruses will be administered to the rats immediately following balloon injury and the neointimal/media ratio and the integrity of VEC will be assessed. This research plan is meant to be part of a Career Development Plan through which the applicant aims to obtain critical knowledge and technical skills. The extraordinary facilities and the availability of advisors and collaborators ensure an optimal environment for the training period. The mentored phase will therefore allow the transition with success to an independent phase. The applicant will continue to develop the final aims of this research project with the long-term goal to develop novel targeted therapies for the treatment of Coronary Artery Disease.

Public Health Relevance

Coronary artery disease (CAD) is currently a leading cause of death worldwide. Despite all the benefits of drug-eluting stents (DES), concerns have been raised over their long-term safety, with particular reference to stent thrombosis due to delayed endothelial cell coverage. This project aims to develop a new therapeutic approach based on microRNA de-targeting strategy that will specifically inhibit restenosis without affecting endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
5K99HL109133-02
Application #
8306029
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (M1))
Program Officer
Scott, Jane
Project Start
2011-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$133,839
Indirect Cost
$9,914
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Santulli, Gaetano; Wronska, Anetta; Uryu, Kunihiro et al. (2014) A selective microRNA-based strategy inhibits restenosis while preserving endothelial function. J Clin Invest 124:4102-14
Santulli, Gaetano; Totary-Jain, Hana (2013) Tailoring mTOR-based therapy: molecular evidence and clinical challenges. Pharmacogenomics 14:1517-26
Totary-Jain, Hana; Sanoudou, Despina; Ben-Dov, Iddo Z et al. (2013) Reprogramming of the microRNA transcriptome mediates resistance to rapamycin. J Biol Chem 288:6034-44
Totary-Jain, Hana; Sanoudou, Despina; Dautriche, Cula N et al. (2012) Rapamycin resistance is linked to defective regulation of Skp2. Cancer Res 72:1836-43