Grant: $331,071 - National Institutes of Health - Jul. 16, 2009
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Award Description: Title: BARTH SYNDROME: A MODEL FOR INVESTIGATING THE ROLE OF CARDIOLIPIN IN MITOCHONDRIA Barth syndrome is an X-linked disorder caused by mutations in the TAZ gene whose protein products, tafazzins, are phospholipid transacylases. The phospholipid most affected by the disease is cardiolipin, a dimeric phospholipid localized exclusively in mitochondria and required for optimal mitochondrial function. Defective cardiolipin metabolism appears to be a major contributing factor underlying the Barth syndrome, which is generally characterized by cardioskeletal myopathy with neutropenia and abnormal mitochondria. Although the cardinal characteristics of Barth syndrome have been clearly defined, the severity of these symptoms are often quite variable, even among patients with identical TAZ mutations, suggesting the existence of additional genetic factors that modify the disease expression. The proposed research utilizes a Drosophila model of Barth syndrome to identify the genetic modifiers of Barth syndrome in genome-wide suppressor screens. By uncovering genetic modifiers of Barth syndrome, we will not only gain new insight into the pathogenetic mechanism of the disease, but also identify potential targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Project Narrative Barth syndrome, a genetic disorder caused by mutations in the TAZ gene, is characterized by cardioskeletal myopathy with neutropenia and abnormal mitochondria. However, the severities of these symptoms are often quite variable, even among patients with identical TAZ mutations, suggesting the existence of additional factors that modify the disease expression. Uncovering these modifiers will not only shed light on the pathogenic mechanism of the disease, but also provide potential targets for therapeutic intervention, which is the long-term goal of the proposed research.
Project Description: The overall purpose of this project is to identify potential targets for therapeutic intervention of the Barth syndrome. Under the parent grant, we have utilized a fruit fly model of Barth syndrome to identify the genetic modifiers of the disease phenotype in genome-wide suppressor screens. Among the suppressors identified so far are two enzymes involved in CL metabolism: one makes CL, the other degrades it. Over expression of the former or genetic inactivation of the latter suppresses the Barth syndrome phenotype in the fly model. We have shown that treatment of Barth syndrome patients' cells in tissue culture with a specific inhibitor of the CL-degrading enzyme partially restores their cardiolipin homeostasis. This ARRA award aims at accelerating the search for drugs that can stimulate CL synthesis and restore CL level in Barth syndrome patients. Specifically, we will pursue the following aims: a) Over express human cardiolipin synthase in Barth patients? lymphoblasts in tissue culture by using a lentiviral gene delivery system and demonstrate its beneficial effects on cellular cardiolipin content, respiration rate, and reactive oxygen species (ROS) production; b) Test drugs known to induce mitochondrial biogenesis for their effects on cardiolipin synthase gene expression, cardiolipin content, respiration rate, and ROS production in Barth patients? lymphoblasts as well as in differentiated C2C12 murine myotubes; c) Develop a quantitative RT-PCR assay for cardiolipin synthase gene expression in 384-well plates format suitable for high-throughput screening; d) Assist in implementation of the assays for high throughput screening in the Molecular Libraries Probe Production Centers Network (MLPCN); e) Perform secondary low throughput screening assays and tests of lead chemical compounds in Barth patients? lymphoblasts in culture. We have begun to carry out experiments within the scope of specific aims (a) and (b), and expect to obtain results in near future.
Jobs Summary: The American Recovery and Reinvestment Act (ARRA) award has resulted in retaining empl# 1010954 (33.2%) as a full-time research scientist employed at NYU Langone Medical Center. He is an experienced researcher, whose employment at NYU Langone Medical Center was about to be terminated due to the current economic recession, is now working full-time on the project supported by ARRA. This award will also allow us to purchase from several US companies equipment and supplies valued at a total of $54,000 over two years, which would contribute to job creation and retention elsewhere in US. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
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