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Vascular Remodeling in Pulmonary Hypertension

Kelly, Neil J (2015) Vascular Remodeling in Pulmonary Hypertension. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kelly, Neil Jnjk41@pitt.eduNJK410000-0003-0455-5348
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairOury, Tim D.tdoury@pitt.eduTDOURY
Committee MemberMars, Wendy M.wmars@pitt.eduWMARS
Committee MemberGoncharova, Elena A.eag59@pitt.eduEAG59
Committee MemberO'Doherty, Robert Mrmo1@pitt.eduRMO1
Thesis AdvisorShapiro, Steven Dshapirosd@upmc.edu
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: 15 Nov 2016 14:29
URI: http://d-scholarship.pitt.edu/id/eprint/25916

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