Kelly, Neil J
(2015)
Vascular Remodeling in Pulmonary Hypertension.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Pulmonary hypertension (PH) is a rare but deadly disease whose victims bear a 40% chance of mortality within the first five years of diagnosis. Although current treatment strategies have been successful at subduing symptoms of PH, they have done little to prolong the survival of those afflicted. PH is characterized histopathologically by, among other characteristics, hyperplasia and hypertrophy of the smooth muscle cells (SMCs) that constitute the medial layer of the pulmonary resistance arteries and which are thought to decrease the compliance and increase the resistance of the pulmonary vasculature. Over time, these changes increase the burden on the right heart and ultimately lead to its failure and patient death. While recent advances have greatly increased our understanding of pulmonary vascular remodeling, knowledge of these mechanisms is far from complete. Furthermore, the translation of putative mechanisms to animal models is hindered by inadequate tools to quantify medial thickening. Here we present a new method for the quantification of vascular remodeling. In addition, we describe a novel mechanism whereby a conserved 20 amino acid peptide (SR20) in the carboxyterminal domain (CTD) of macrophage elastase (MMP12) induces the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL is known to preferentially induce apoptosis in tumor cells, and we demonstrate the efficacy of SR20 and the MMP12 CTD in vitro and in vivo as a cytotoxic agent against tumor cells. TRAIL is also known to paradoxically increase the proliferation of vascular SMCs, and we present evidence that the MMP12 CTD increases the proliferation of pulmonary arterial SMCs through upregulation of TRAIL with potential links to PH. Finally, we present the results of a genome-wide association study in 36 inbred and wild-derived mouse strains exposed to a chronic high-fat diet-induced model of PH to uncover novel candidate genes linked to PH pathogenesis. The results of these studies should aid investigators in all areas of basic PH research through the provision of superior methods. Meanwhile, the identification of the MMP12 CTD as a mitogen for pulmonary SMCs, and the identification of genomic regions linked to PH development, will help improve our understanding of PH pathogenesis.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
7 August 2015 |
| Date Type: |
Publication |
| Defense Date: |
29 July 2015 |
| Approval Date: |
7 August 2015 |
| Submission Date: |
7 August 2015 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
154 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Pulmonary Hypertension, Wall Thickness, Vascular Remodeling |
| Date Deposited: |
07 Aug 2015 19:56 |
| Last Modified: |
07 Aug 2020 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/25916 |
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