Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation
Thesis (Sc. D.)--Harvard-MIT Division of Health Sciences and Technology, 2004.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2005
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| Online Access: | http://hdl.handle.net/1721.1/18063 |
| _version_ | 1811094474004103168 |
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| author | Binello, Emanuela |
| author2 | Richard N. Mitchell. |
| author_facet | Richard N. Mitchell. Binello, Emanuela |
| author_sort | Binello, Emanuela |
| collection | MIT |
| description | Thesis (Sc. D.)--Harvard-MIT Division of Health Sciences and Technology, 2004. |
| first_indexed | 2024-09-23T16:00:33Z |
| format | Thesis |
| id | mit-1721.1/18063 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T16:00:33Z |
| publishDate | 2005 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/180632019-04-10T15:15:11Z Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation Binello, Emanuela Richard N. Mitchell. Harvard University--MIT Division of Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology. Thesis (Sc. D.)--Harvard-MIT Division of Health Sciences and Technology, 2004. Includes bibliographical references (leaves 138-160). Peroxisome proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily; two major isoforms, PPARα and PPAR[gamma], are primarily involved in lipid and glucose homeostasis. However, evidence also suggests roles for PPARs in regulating inflammation and atherosclerosis, and prompted investigation into the efficacy of PPAR agonists in parenchymal rejection (PR) and transplantation-associated arteriosclerosis (TxAA). Four different PPAR agonists (fenofibrate and Wy14643 for PPARα; BRL69453 and 15-deoxy-[delta]¹⁴̹⁶ Prostaglandin-J₂ for PPAR[gamma]) in an in vitro model of the alloresponse all demonstrated a robust and substantial attenuation of IFN[gamma], a cytokine that critically affects both rejection and TxAA. This occurred in a dose-dependent manner, independent of known IFN[gamma]-inducing cytokines. At the same times, PPAR activation increased the overall expression of chemokines but substantially decreased expression of two relevant chemokine receptors. Of the four agonists tested, fenofibrate, a largely PPARα-specific agonist, had the best profile of IFN[gamma] production to chemokine and chemokine receptor expression. At early time points after cardiac transplantation, fenofibrate administration showed findings consistent with those seen in vitro, including a tendency to reduce IFN[gamma]. However, long-term fenofibrate treatment significantly increased graft IFN[gamma] expression and inflammatory cell infiltration, thereby augmenting PR without ameliorating TxAA. Congenital deficiency of PPARα confirmed that the receptor plays a regulatory role in IFN[gamma] expression but is not necessary for graft infiltration by inflammatory cells. The findings constitute the first examination of the efficacy of PPAR agonists in (cont.) solid-organ transplantation and suggest that in order to fully realize the beneficial anti-inflammatory effects of fenofibrate, additional strategies must be employed to inhibit graft inflammatory cell infiltration. Finally, a novel immunologic research tool based on the boron neutron capture reaction is proposed. by Emanuela Binello. Sc.D. 2005-06-02T19:49:39Z 2005-06-02T19:49:39Z 2004 2004 Thesis http://hdl.handle.net/1721.1/18063 57509271 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 160 leaves 14357912 bytes 14379684 bytes application/pdf application/pdf application/pdf Massachusetts Institute of Technology |
| spellingShingle | Harvard University--MIT Division of Health Sciences and Technology. Binello, Emanuela Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation |
| title | Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation |
| title_full | Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation |
| title_fullStr | Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation |
| title_full_unstemmed | Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation |
| title_short | Role of peroxisome proliferator-activated receptors in mechanisms of rejection in heart transplantation |
| title_sort | role of peroxisome proliferator activated receptors in mechanisms of rejection in heart transplantation |
| topic | Harvard University--MIT Division of Health Sciences and Technology. |
| url | http://hdl.handle.net/1721.1/18063 |
| work_keys_str_mv | AT binelloemanuela roleofperoxisomeproliferatoractivatedreceptorsinmechanismsofrejectioninhearttransplantation |