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Regulation of Acvrl1 and its Implications in Hereditary Hemorrhagic Telangiectasia

Dholakia, Gayatri (2024) Regulation of Acvrl1 and its Implications in Hereditary Hemorrhagic Telangiectasia. Master's Thesis, University of Pittsburgh. (Unpublished)

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Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder inherited in an autosomal dominant pattern that affects at least 1 in 5000 people worldwide. It is characterized by the presence of arteriovenous malformations (AVMs), abnormal connections between arteries and veins lacking capillary beds, which pose life-threatening risks including stroke and heart failure. HHT is caused primarily by heterozygous loss-of-function mutations in ENG (endoglin), which causes HHT1, or ACVRL1 (ALK1), which causes HHT2. ENG and ALK1 act in a common pathway: ENG is an accessory receptor that facilitates bone morphogenetic protein (BMP) binding to ALK1, a signaling receptor. Despite an understanding of the affected signaling pathway, there are currently no targeted therapeutics for HHT. We suggest that one potential therapeutic approach is to enhance the expression of ACVRL1 to slow development and/or progression of AVMs, particularly in HHT1 patients, in whom ACVRL1 is intact. To investigate the regulation of acvrl1 gene expression, I am interrogating the activity of putative cis regulatory elements in zebrafish. ACVRL1 is expressed predominantly in endothelial cells, specifically arterial endothelial cells, and its expression depends on blood flow. Using a stable zebrafish line, I have determined that deletion of a small segment (667 bp) of intron 1 implicated in flow responsiveness is not necessary for basal or flow induced acvrl1 expression. Additionally, using CRISPR/Cas9, I have generated two new lines in which putative enhancers, identified by single cell ATAC-seq as being enriched (more open) in 5 day-post fertilization zebrafish embryonic arterial endothelial cells, are deleted. Thus far, I have established parental (P0) lines with large deletions in the 5’ intergenic region (2 lines each targeting 2 putative enhancers) and intron 1 (1 line targeting 2.7 kb of this intron). Further work is required to identify founders for each line and determine the necessity of these cis elements in basal and flow induced acvrl1 expression in their offspring. Identifying these elements will offer valuable insights into strategies for enhancing ACVRL1 expression to counteract endoglin loss in HHT1 patients. This research holds public health significance because it may lead to development of targeted gene therapies for HHT patients.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dholakia, Gayatrigad58@pitt.eduGad58
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoman, Bethromanb@pitt.eduromanb
Committee MemberUrban, Zsolturbanz@pitt.eduurban
Committee MemberLord, Nathanndlord@pitt.edundlord
Date: 16 May 2024
Date Type: Publication
Defense Date: 19 April 2024
Approval Date: 16 May 2024
Submission Date: 25 April 2024
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 63
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: acvrl1, Hereditary Hemorrhagic Telangiectasia
Date Deposited: 16 May 2024 19:41
Last Modified: 16 May 2024 19:41


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