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The Joseph Stokes, Jr., Research Institute Project 1: Biocompatible heterograft biomaterials Robert Levy, PI Aims 1.Chemistry and crosslinking using triglycidyl.

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Presentation on theme: "The Joseph Stokes, Jr., Research Institute Project 1: Biocompatible heterograft biomaterials Robert Levy, PI Aims 1.Chemistry and crosslinking using triglycidyl."— Presentation transcript:

1 The Joseph Stokes, Jr., Research Institute Project 1: Biocompatible heterograft biomaterials Robert Levy, PI Aims 1.Chemistry and crosslinking using triglycidyl amine (TGA) to prepare bioprosthetic heart valves: Rapoport et al, Biomaterials. 2007;28(4): Biomechanical effects of TGA crosslinking: Sacks et al, Ann Thorac Surg. 2006;82(4): Extracellular matrix interactions—TGF  1 related calcification mechanisms: Clark-Greuel et al, Ann Thorac Surg. 2007;83(3):946-53

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

3 The Joseph Stokes, Jr., Research Institute Reaction of MABP with residual epoxy groups

4 The Joseph Stokes, Jr., Research Institute MABP interactions with Ca/phosphates: The TGA-MABP reaction product is an inhibitor of Ca-phosphate formation

5 The Joseph Stokes, Jr., Research Institute Aim 3: Proposed model for 5-HT/Fenfluramine heart valve cell and/or macrophage interactions With resulting transcriptional effects on cytokines, proliferation, ECM TGF  1

6 The Joseph Stokes, Jr., Research Institute Serotonin (5HT) Dose Response for Mitral Valve Interstitial 5HT-Receptor Signaling: ERK Phosphorylation Studies

7 The Joseph Stokes, Jr., Research Institute Fenfluramine does not directly stimulate 5HTR, but by preventing transporter processing increases signaling activity

8 The Joseph Stokes, Jr., Research Institute CanineHuman Fenfluramine (M): 5-HT: Serotonin transporter blockade using fenfluramine results in increased Erk1/2 phosphorylation Erk1/p Erk2/p

9 The Joseph Stokes, Jr., Research Institute Fluoxetine also does not directly stimulate 5HTR, but by preventing transporter processing increases signaling activity

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

11 The Joseph Stokes, Jr., Research Institute 5HT Effects on MVIC proliferation: 3[H]Thymidine Incorporation

12 The Joseph Stokes, Jr., Research Institute 5HT Effects on MVIC extracellular matrix: 3[H]Proline Incorporation

13 The Joseph Stokes, Jr., Research Institute ANOVA (non-parametric) p=0.001 ANOVA (non-parametric) p= HT Effects on MVIC extracellular matrix: 3[H]Glucosamine Incorporation Secreted Cellular/ECM

14 The Joseph Stokes, Jr., Research Institute 3 H-5HT Uptake by Mitral Valve Interstitial Cells:5HTT Functionality

15 The Joseph Stokes, Jr., Research Institute 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 The Joseph Stokes, Jr., Research Institute 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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