Toward Humanized Mouse Models of Mitochondrial Disease
Abstract
Central Critical Problem to Be Addressed: Mutations in mitochondrial DNA (mtDNA) are a prevailing cause of mitochondrial disease, which can be fatal and can affect anybody, including military personnel and their families. Currently, treatment options for mitochondrial disease are limited to palliative care. Animal models of human disease are instrumental in developing and testing new drugs. Currently, no faithful mouse models are available to facilitate research and drug development for mitochondrial disease (the critical problem, broad). Present day methods for generating mouse models of mitochondrial disease require availability of mouse cells, which carry mtDNA mutations equivalent to those found in human disease. However, neither such cells nor efficient methods to generate them exist today (the critical problem, more specific). Innovation: Here, we propose to radically alter the conventional way of generating mouse models of mitochondrial disease by proposing that mouse models can be created using patient mtDNA. Common wisdom suggests that this is impossible, first and foremost, due to the inability of the mouse cells to maintain human mtDNA. Our hypothesis, however, is that rejection of human mtDNA in mouse cells can be overcome by introducing into these cells several human genes responsible for mtDNA maintenance. It is important to note here that the latest findings in the field of mtDNA research support feasibility of this approach. No attempts to overcome rejection of mtDNA of one species of animals in cells from another species have been reported in the scientific literature to date (hence, the proposed studies are the first of a kind -- innovation). Therefore, in this application we propose to initiate a new line of research. The proposed studies constitute the first step towards shifting the paradigm of how mouse models of mitochondrial disease caused by mtDNA mutations are generated. This research will provide new insights into how mtDNA rejection mechanisms work and which proteins are responsible for rejection. It will also provide new insights into poorly studied subject of interaction and coordination between nuclear and mitochondrial genomes. The Ultimate Applicability and Impact: The ultimate outcome of the proposed line of research is a "humanized" murine platform for modeling mitochondrial disease using patient mtDNA. This platform will trivialize the existing crippling bottleneck, which so far prevented generation of accurate mouse models of mitochondrial disease caused by mtDNA mutations. It will do so by replacing requirement for availability of mouse mtDNA carrying mutations equivalent to those found in human disease with human mtDNA, which is abundant in the blood of patients. In the short term, the proposed studies will improve our understanding of mtDNA replication. They will also stimulate research into the poorly understood mechanisms of interaction and coordination between nuclear and mitochondrial genomes by providing a novel platform and tools for these studies. If successful, the proposed studies will lay the foundation for projects aimed at optimization of transcription, translation, and/or respiratory chain function (as necessary) in humanized mouse cells. In the long term, these studies will lead to an emergence of a conceptually new approach to modeling mitochondrial disease in mice by supplying chimeric "humanized" mice. These mice, in which normal mitochondrial function will be supported by human, rather than murine mtDNA, will serve as a novel platform for the generation of mouse models of human disease using readily available patient mitochondria containing mutant mtDNA. The availability of accurate mouse models of mitochondrial disease enabled by this new platform will in turn serve as both an enabling and stimulating factor for research into mechanisms of mitochondrial disease. These models will also serve as a platform for the development and testing
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610096
Entities
People
- Mikhail F Alexeyev
Organizations
- United States Army
- University of South Alabama