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Project 1: Biocompatible heterograft biomaterials Robert Levy, PI

Project 1: Biocompatible heterograft biomaterials Robert Levy, PI. Aims Chemistry and crosslinking using triglycidyl amine (TGA) to prepare bioprosthetic heart valves: Rapoport et al, Biomaterials. 2007;28(4):690-9 2. Biomechanical effects of TGA crosslinking:

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Project 1: Biocompatible heterograft biomaterials Robert Levy, PI

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  1. Project 1: Biocompatible heterograft biomaterials Robert Levy, PI • Aims • Chemistry and crosslinking using triglycidyl amine (TGA) • to prepare bioprosthetic heart valves: • Rapoport et al, Biomaterials. 2007;28(4):690-9 • 2. Biomechanical effects of TGA crosslinking: • Sacks et al, Ann Thorac Surg. 2006;82(4):1369-77 • 3. Extracellular matrix interactions—TGFb1 related • calcification mechanisms: • Clark-Greuel et al, Ann Thorac Surg. 2007;83(3):946-53

  2. Project 1 Triglycidyl Amine (TGA) • Reacts irreversibly with lysine, methionine, cystine, histidine • Results in biomechanical properties superior to glutaraldehyde • Biocompatibility—supports cellular growth of all cardiovascular cell types

  3. Reaction of MABP with residual epoxy groups

  4. MABP interactions with Ca/phosphates: The TGA-MABP reaction product is an inhibitor of Ca-phosphate formation

  5. Aim 3: Proposed model for 5-HT/Fenfluramine heart valve cell and/or macrophage interactions TGFb1 With resulting transcriptional effects on cytokines, proliferation, ECM

  6. Serotonin (5HT) Dose Response for Mitral Valve Interstitial 5HT-Receptor Signaling: ERK Phosphorylation Studies

  7. Fenfluramine does not directly stimulate 5HTR, but by preventing transporter processing increases signaling activity

  8. Serotonin transporter blockade using fenfluramine results in increased Erk1/2 phosphorylation Canine Human Fenfluramine (M): 5-HT: Erk1/p Erk2/p

  9. Fluoxetine also does not directly stimulate 5HTR, but by preventing transporter processing increases signaling activity

  10. Ketanserin, a 5HT2A receptor antagonist, inhibit signaling in both human and canine mitral valve interstitial cells Human PD-MEK inhibitor K-5HT2A antagonist SB41-5HT2B antagonist SB53-5HT2B&2C antagonist W-5HT1A antagonist GR-5HT1B antagonist BRL-5HT1D antagonist Canine

  11. 5HT Effects on MVIC proliferation: 3[H]Thymidine Incorporation

  12. 5HT Effects on MVIC extracellular matrix: 3[H]Proline Incorporation

  13. 5HT Effects on MVIC extracellular matrix: 3[H]Glucosamine Incorporation Cellular/ECM Secreted ANOVA (non-parametric) p=0.002 ANOVA (non-parametric) p=0.001

  14. 3H-5HT Uptake by Mitral Valve Interstitial Cells:5HTT Functionality

  15. Work in progress Effects of fenfluramine, fluoxetine & ketanserin on 5HT-related endpoints in cell culture Canine clinical trial treating myxomatous mitral valve disease with ketanserin: MTA with Jannsen under negotiation Genotyping patients with mitral valve disease: re. 5HTT polymorphisms, HUP IRB Protocol is now approved

  16. Collaborators Jeanne Connolly James Fulmer Joseph Gorman, M.D., HUP Robert Gorman, M.D., HUP Mark Oyama, DVM, Penn Vet. School H. Scott Rapoport Ken Ryan, Ph.D. Michael Sacks, Ph.D., Univ.Pittsburgh Stan Stachelek, Ph.D.

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