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Expression of alk1 is regulated by a positive feedback mechanism involving blood flow and circulating ligand

Kunz, Amy (2016) Expression of alk1 is regulated by a positive feedback mechanism involving blood flow and circulating ligand. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

ALK1, a TGF-β type I receptor serine/threonine kinase, is critical for proper vascular development. Heterozygous loss of ALK1 results in the vascular disorder, hereditary hemorrhagic telangiectasia type 2 (HHT2), which is characterized by the development of arteriovenous malformations (AVMs) and affects 1 in 5,000 people worldwide. HHT is thought to be caused by a haploinsufficiency and therefore delineating how ALK1 is regulated could provide avenues for targeted and effective clinical interventions. In the zebrafish model organism, alk1 is expressed in arterial endothelial cells of vessels leading away from the heart. We have learned that alk1 expression closely correlates with the presence of blood flow, but which component of blood flow is responsible for regulation is unknown. I propose that flow is required for activation of a positive feedback mechanism by which Bmp10 – a circulating ligand of Alk1 receptors that is produced by the heart and secreted into the bloodstream – through Alk1 activation maintains arterial alk1 expression at the level of transcription. In this work, I define the spatiotemporal relationship between cessation and restoration of blood flow and alk1 expression and show that flow-mediated alk1 expression is regulated at the transcriptional level. Finally, I provide evidence that intact Bmp10/Alk1 signaling is required to maintain alk1 mRNA expression. I hypothesize that this effect is driven by a gradient of Bmp10 ligand established by blood flow that triggers a positive feedback mechanism initiated by Bmp10/Alk1 signaling. The goal of my work is to understand the mechanism of ALK1 regulation in order to progress toward the goal of targets and effective clinical management for HHT patients. HHT is a relatively common genetic disease that often goes underdiagnosed due to its variable presentation even among members of the same family, hence studying this complex disease is significant for practice of public health.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kunz, Amybieryamy@pitt.eduBIERYAMY
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoman, Beth Lromanb@pitt.eduROMANB
Committee MemberHukriede, Neil Ahukriede@pitt.eduHUKRIEDE
Committee MemberUrban, Zsolturbanz@pitt.edu
Committee MemberDurst, Andreadursta@pitt.edu
Date: 29 June 2016
Date Type: Publication
Defense Date: 19 April 2016
Approval Date: 29 June 2016
Submission Date: 31 March 2016
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 59
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Alk1, zebrafish, vasculature, HHT
Date Deposited: 29 Jun 2016 18:10
Last Modified: 01 May 2018 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/27513

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