This project is designed to develop a novel mouse model of human mitochondrial disease. Genetic engineering and molecular biological techniques will be utilized to create heteroplasmic """"""""transmitochondrial"""""""" mice harboring a mutant mitochondrial genome. This model and the procedures for mitochondrial transfer will be of considerable importance toward our understanding of a specific mitochondrial mutation, as well as leading to the development of novel strategies and therapies for human metabolic diseases influenced by aberrations in mitochondrial function or mutation. In pilot experiments, the ability to create transmitochondrial mouse models that transmit the heteroplasmic state to offspring in maternal lineages was identified. With the advent of gene transfer technologies and PCR-based procedures, this project will target the development of technology to establish a mouse model harboring a directed mitochondria DNA (mtDNA) deletion.
Specific Aims i nclude: (1) development and optimization of mitochondria transfection procedures, (2) transfer of transfected mitochondria (or cells) into mouse ova to produce heteroplasmic transmitochondrial mice that will recapitulate a deletion associated with human mtDNA-based disease - for which no animal model exists for study, and (3) characterization of transmitochondrial mouse lineages created over the course of this project. Production of heteroplasmic transmitochondrial deletion mutants will be a critical first step, facilitating the study of mitochondrial function and disease progression. Initially, this model will serve to explore disease pathogenesis and mitochondrial dynamics in an in vivo system. Ultimately, transmitochondrial mouse models will be used to explore the role of the mitochondrial genome in human metabolic disease processes and in the development of novel human gene therapies.
| Irwin, Michael H; Parameshwaran, Kodeeswaran; Pinkert, Carl A (2013) Mouse models of mitochondrial complex I dysfunction. Int J Biochem Cell Biol 45:34-40 |
| Dunn, David A; Pinkert, Carl A (2012) Nuclear expression of a mitochondrial DNA gene: mitochondrial targeting of allotopically expressed mutant ATP6 in transgenic mice. J Biomed Biotechnol 2012:541245 |
| Dunn, David A; Cannon, Matthew V; Irwin, Michael H et al. (2012) Animal models of human mitochondrial DNA mutations. Biochim Biophys Acta 1820:601-7 |
| Cannon, M V; Dunn, D A; Irwin, M H et al. (2011) Xenomitochondrial mice: investigation into mitochondrial compensatory mechanisms. Mitochondrion 11:33-9 |
| Parameshwaran, Kodeeswaran; Irwin, Michael H; Steliou, Kosta et al. (2010) D-galactose effectiveness in modeling aging and therapeutic antioxidant treatment in mice. Rejuvenation Res 13:729-35 |
| Ingraham, Christopher A; Burwell, Lindsay S; Skalska, Jolanta et al. (2009) NDUFS4: creation of a mouse model mimicking a Complex I disorder. Mitochondrion 9:204-10 |
| Nadtochiy, Sergiy M; Burwell, Lindsay S; Ingraham, Christopher A et al. (2009) In vivo cardioprotection by S-nitroso-2-mercaptopropionyl glycine. J Mol Cell Cardiol 46:960-8 |
| Pogozelski, Wendy K; Fletcher, Leah D; Cassar, Carolyn A et al. (2008) The mitochondrial genome sequence of Mus terricolor: comparison with Mus musculus domesticus and implications for xenomitochondrial mouse modeling. Gene 418:27-33 |
| Welle, Stephen; Bhatt, Kirti; Pinkert, Carl A et al. (2007) Muscle growth after postdevelopmental myostatin gene knockout. Am J Physiol Endocrinol Metab 292:E985-91 |
| Takeda, Kumiko; Tasai, Mariko; Iwamoto, Masaki et al. (2005) Microinjection of cytoplasm or mitochondria derived from somatic cells affects parthenogenetic development of murine oocytes. Biol Reprod 72:1397-404 |
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