This is a proposal to create a biologically active prosthetic arterial graft incorporating gene silencing to an antithrombotic and pro-angiogenic surface. The research team is unique in its cohesiveness and breadth of expertise including textiles, polymers, cell biology, molecular biology, and surgery, all with an established focus on vascular grafts. This project builds on our long-standing work where we have 1) characterized the lesion of anastomotic neointimal hyperplasia (AIH) downstream of the prosthetic graft, 2) established the role of blood flow-surface interaction in AIH pathogenesis, 3) applied biologic modification to the graft surface by incorporating antithrombotic (rHirudin) and endothelial cell growth factor (VEGF) to delay thrombus formation and improve endothelialization, and 4) determined the unique gene signature associated with AIH development, including identification of high profile pathogenic targets. The goals of the current proposal are to 1) Validate the involvement of MARCKS, CDH11, and TSP2 in the pathogenesis of AIH, by means of in vitro loss-of-function studies in endothelial and smooth muscle cells using siRNA, 2) Create a bioactive electrospun nanofibrous graft material and determine optimal physical properties that it requires for effective siRNA delivery to the vasculature under pulsatile flow and operating room conditions and, 3) implant the graft prototype in a large canine animal model, after preliminary testing in a rat model, and determine sequentially its potential to deliver siRNA, effectively induce gene silencing and positively impact the development of AIH lesions, including graft healing and patency. This is a stepwise study bringing to bear a unique and appropriately broad range of expertise on the effective application of gene silencing to improve the outcome of prosthetic arterial grafts. The information will also be of interest in the larger use of materials to deliver siRNA for therapeutic purposes.

Public Health Relevance

This is a proposal to create an improved bypass graft to treat cardiovascular disease. A new material that mimics normal blood vessel will be used to carry agents that silence the expression of tissue genes that cause blockage of existing graft materials. It will greatly improve the treatment of atherosclerosis in the heart and circulation system. More general benefits will come for using biomaterials to deliver gene silencing for other purposes such as tissue repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL021796-29
Application #
8605901
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Baldwin, Tim
Project Start
1987-07-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
29
Fiscal Year
2014
Total Cost
$533,883
Indirect Cost
$169,788
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
McGillicuddy, Fiona C; Moll, Herwig P; Farouk, Samira et al. (2014) Translational studies of A20 in atherosclerosis and cardiovascular disease. Adv Exp Med Biol 809:83-101
da Silva, Cleide Gonçalves; Minussi, Darlan Conterno; Ferran, Christiane et al. (2014) A20 expressing tumors and anticancer drug resistance. Adv Exp Med Biol 809:65-81
Pradhan-Nabzdyk, Leena; Huang, Chenyu; LoGerfo, Frank W et al. (2014) Current siRNA targets in atherosclerosis and aortic aneurysm. Discov Med 17:233-46
Pradhan-Nabzdyk, Leena; Huang, Chenyu; LoGerfo, Frank W et al. (2014) Current siRNA targets in the prevention and treatment of intimal hyperplasia. Discov Med 18:125-32
Nabzdyk, Christoph S; Chun, Maggie C; Oliver-Allen, Hunter S et al. (2014) Gene silencing in human aortic smooth muscle cells induced by PEI-siRNA complexes released from dip-coated electrospun poly(ethylene terephthalate) grafts. Biomaterials 35:3071-9
Nabzdyk, Christoph S; Chun, Maggie; Pradhan, Leena et al. (2011) High throughput RNAi assay optimization using adherent cell cytometry. J Transl Med 9:48
Yoshida, Shunsuke; Nabzdyk, Christoph S; Pradhan, Leena et al. (2011) Thrombospondin-2 gene silencing in human aortic smooth muscle cells improves cell attachment. J Am Coll Surg 213:668-76
Andersen, Nicholas D; Chopra, Atish; Monahan, Thomas S et al. (2010) Endothelial cells are susceptible to rapid siRNA transfection and gene silencing ex vivo. J Vasc Surg 52:1608-15
Monahan, Thomas S; Andersen, Nicholas D; Martin, Michelle C et al. (2009) MARCKS silencing differentially affects human vascular smooth muscle and endothelial cell phenotypes to inhibit neointimal hyperplasia in saphenous vein. FASEB J 23:557-64
Andersen, Nicholas D; Monahan, Thomas S; Malek, Junaid Y et al. (2007) Comparison of gene silencing in human vascular cells using small interfering RNAs. J Am Coll Surg 204:399-408

Showing the most recent 10 out of 36 publications