Pathogenesis of Tafazzin Deficiency in a Murine Model of Barth Syndrome

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Material Information

Title:
Pathogenesis of Tafazzin Deficiency in a Murine Model of Barth Syndrome
Physical Description:
1 online resource (134 p.)
Language:
english
Creator:
Soustek, Meghan S
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Genetics (IDP)
Committee Chair:
BYRNE,BARRY JOHN
Committee Co-Chair:
LEWIN,ALFRED S
Committee Members:
SWANSON,MAURICE S
WALTER,GLENN A

Subjects

Subjects / Keywords:
aav -- bths -- exercise -- mitochondria -- tafazzin
Genetics (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Barth Syndrome (BTHS) is an X-linked mitochondrial disease that is linked to mutations within the tafazzin (TAZ) gene. BTHS patients exhibit cardiomyopathy, muscle weakness, and neutropenia. Much of what is known about Barth Syndrome has been elucidated through studying TAZ deficient yeast, fruit fly, and zebrafish models as well as BTHS patient cell lines. While these model systems have proven to be instrumental in understanding the role of TAZ in the pathogenesis of BTHS, there remained a clear necessity to develop a mammalian model to fully appreciate the role of TAZ in cardiac and skeletal muscle function. Here we describe the characterization of the first mammalian model of BTHS. The model is a doxycycline shRNA-inducible TAZ knockdown mouse (TAZKD). Upon induction of the TAZ-specific shRNA, TAZ deficiency led to the absence of tetralineoyl-CL in cardiac tissue. Physiological measurements demonstrated a reduction in contractile strength of the soleus and a reduction in cardiac left ventricular ejection fraction of TAZKD mice. To further characterize the TAZKD model, we sought to determine if a swim-training regimen would exacerbate the cardiac and skeletal muscle phenotypes. Our data suggest endurance training did not accelerate cardiac dysfunction, but resulted in beneficial physiological effects in young TAZKD mice. Although treatment has improved for BTHS patients, cardiac dysfunction can be fatal. As BTHS is due to a single gene defect, we proposed to use adeno-associated viral vector delivery to replace deficient TAZ. TAZ has been shown to act as an acyltransferase involved in the remodeling of CL. Based on the cyclic process of CL remodeling, over-expression of TAZ may be toxic; therefore, in order to obtain appropriate levels of gene expression, we identified and compared the activity of the endogenous promoter with that of a tissue-restricted promoter, desmin (DES). Finally, we demonstrated in vitro, that upon transducing BTHS patient cells with an AAV vector expressing TAZ, TAZ is localized to the mitochondria and tetralineoyl-CL content is dramatically increased. Although further investigation should be performed to quantify MLCL:CL, this study has therapeutic implications for the future use of gene therapy for the treatment of BTHS.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Meghan S Soustek.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: BYRNE,BARRY JOHN.
Local:
Co-adviser: LEWIN,ALFRED S.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2016-05-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2014
System ID:
UFE0046458:00001