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Zebrafish bmp10 mutants as a model for hereditary hemorrhagic telangiectasia - associated high output heart failure

Li, Bijun (2019) Zebrafish bmp10 mutants as a model for hereditary hemorrhagic telangiectasia - associated high output heart failure. Master's Thesis, University of Pittsburgh. (Unpublished)

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Hereditary hemorrhagic telangiectasia (HHT) is an inherited disease caused by impaired signaling through the bone morphogenetic protein (BMP) receptor, ALK1, and is characterized by fragile, direct connections between arteries and veins, called arteriovenous malformation (AVMs). AVMs can form in skin, mucous membranes, brain, lung, and liver and can be life-threatening if severe shunting or rupture occurs. For example, severe liver AVMs result in low systemic vascular resistance, which can lead to a transient, compensatory high-output cardiac state followed by decompensation and heart failure. The only treatment for HHT-associated high-output heart failure (HOHF) is liver transplant. As such, the need for targeted therapeutics is clear, yet little is known about the pathological progression of HOHF. Here, I describe zebrafish bmp10 mutants as a useful animal model of HHT-associated, age-dependent HOHF. bmp10 encodes one of three Alk1 ligands in zebrafish, and homozygous bmp10 mutants develop dilated and hemorrhagic skin vessels, edema, and enlarged hearts as early as six weeks of age. bmp10 mutants with severe early-onset vascular phenotype exhibit high cardiac output, cardiomyocyte (CM) disorganization, and early death, whereas those with later-onset vascular lesions show milder heart phenotype. At the cellular level, bmp10 mutant hearts may have CM hypertrophy and increased proliferating cell nuclear antigen (PNCA) signal. Our long-term goal is to use this zebrafish model to understand the mechanisms involved in cardiac compensation and in the pathological progression to heart failure, which may aid in design of medical therapies to prevent HOHF in HHT patients. Also, in addition to HHT, HOHF is identified in some common diseases, such as morbid obesity, anemia and sepsis, and HOHF is associated with high mortality. Hence, studying this type of heart failure is of public health significance.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Li, Bijunbil23@pitt.edubil230000-0002-2784-5279
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRoman, Beth
Committee MemberUrban,
Committee MemberKuhn,
Committee MemberSt Hilaire,
Date: 24 June 2019
Date Type: Publication
Defense Date: 28 March 2019
Approval Date: 24 June 2019
Submission Date: 3 April 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 47
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: high output heart failure, hereditary hemorrhagic telangiectasia, bmp10, zebrafish
Date Deposited: 24 Jun 2019 20:50
Last Modified: 01 May 2021 05:15


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