Cardiovascular disease accounts for nearly one third of deaths globally, and coronary artery disease remains the number one cause of death in the United States. Diabetes increases the risk of fatal CAD and peripheral vascular disease. Vascular smooth muscle cell (VSMC) proliferation and migration contribute to coronary artery disease and are the major causes of coronary artery in-stent restenosis and accelerated arteriopathy following cardiac transplantation. Drug-eluting stents (rapamycin-sirolimus) was a major advance in the treatment of CAD, causing significant reduction in the incidence of restenosis. However, diabetic patients still had a two-fold higher incidence of restenosis compared to non-diabetics. We will use rapamycin as a """"""""molecular probe"""""""" to dissect pathways that govern VSMC growth and migration.
Aim one will test the hypothesis that diabetes leads to an overstimulation of the PI3K/Akt/Foxo pathway', decreasing p27Kip1 gene expression, conferring relative rapamycin resistance. We will examine the effects of rapamycin on the proliferation and migration of VSMC grown in the presence of high glucose Jeptin treated, then on the formation of neointimal hyperplasia following arterial injury in different mouse models of diabetes.
Aim two will determine whether blocking multiple growth pathways using rapamycin and inhibitors of Akt/PI3K can synergistically inhibit intimal proliferation following vascular injury in diabetic/obesity animal models. We will test new drug combinations in animal model in which resistance to rapamycin's antiproliferative effect was observed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL088815-03
Application #
7816769
Study Section
Special Emphasis Panel (ZRG1-F10-Q (21))
Program Officer
Meadows, Tawanna
Project Start
2008-05-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$53,810
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Totary-Jain, Hana; Marks, Andrew R (2013) MicroRNAs and the cellular response to rapamycin: potential role in diagnosis and therapy. Cell Cycle 12:861-2
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
Santulli, Gaetano; Totary-Jain, Hana (2013) Tailoring mTOR-based therapy: molecular evidence and clinical challenges. Pharmacogenomics 14:1517-26
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
Marx, Steven O; Totary-Jain, Hana; Marks, Andrew R (2011) Vascular smooth muscle cell proliferation in restenosis. Circ Cardiovasc Interv 4:104-11
Shan, Jian; Nguyen, Thomas B; Totary-Jain, Hana et al. (2008) Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors. Proc Natl Acad Sci U S A 105:19006-11