| Project/Area Number |
14035101
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
|
| Allocation Type | Single-year Grants |
|---|
| Review Section |
Biological Sciences
|
|---|
| Research Institution | University of Tsukuba |
|---|
Principal Investigator |
HAYASHI Jun-ichi University of Tsukuba, Doctoral Program in Functional Biosciences, Graduate School of Life and Environmental Sciences, Professor (60142113)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OHTA Shigeo Nippon Medical School, Graduate School of Medicine, Institute of Development and Aging Sciences, Professor (00125832)
|
|---|
| Project Period (FY) |
2002 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥74,400,000 (Direct Cost: ¥74,400,000)
Fiscal Year 2006: ¥13,300,000 (Direct Cost: ¥13,300,000)
Fiscal Year 2005: ¥13,300,000 (Direct Cost: ¥13,300,000)
Fiscal Year 2004: ¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 2003: ¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 2002: ¥16,000,000 (Direct Cost: ¥16,000,000)
|
|---|
| Keywords | Mitochondrial diseases / Mouse Mutated mtDNA / Disease Model Mice / Gene Therapy of Fertilized Egg / Mitochondrial tRNA Expression / ミトコンドリア遺伝病 / ミトコンリア間相互作用 / 臨床症状の多様性 / クローンマウス / 核移植による遺伝子治療 / 核ミトコンドリア相互作用 / マウス突然変異型mtDMA |
|---|
| Research Abstract |
(1) Sato, A. et al. Proc. Natl. Acad. Sci. USA 102: 16765-16770. 2005
Pathogenic mutations in mtDNAs have been shown to be responsible for expression of respiration defects and resultant expression of mitochondrial diseases. This study directly addressed the issue of gene therapy of mitochondrial diseases using nuclear transplantation of zygotes of trans-mitochondria mice (mito-mice). Mito-mice expressed respiration defects and mitochondrial diseases due to accumulation of mtDNA carrying a large-scale deletion (ΔmtDNA). Second polar bodies were used as biopsy samples for diagnosis of mtDNA genotypes of mito-mouse zygotes. Nuclear transplantation was carried out from mito-mouse zygotes to enucleated normal zygotes, and was shown to rescue all the F_0 progenies from expression of respiration defects throughout their lives. This -procedure should be applicable to patients with mitochondrial diseases for preventing their children from the diseases.
(2) Sato, A. et al. Proc. Natl. Acad. Sci.
… More
USA 102: 6057-6062. 2005
The problem of whether recombinant mtDNAs are created in mammalian cells has been controversial for many years. We show convincing evidence for the very rare creation of recombinant mtDNA haplotypes by isolating human somatic hybrid cells and by generating mice carrying two different mtDNA haplotypes. Such an extremely low frequency of mtDNA recombination does not require any revision of important concepts on human evolution that are based on its absence.
(3) Liqin, C., et al. Nature Genet. 39:386-390, 2007
The observations of rapid shifts in mtDNA variants between generations have originated the bottleneck theory. A prevalent hypothesis which has long been proposed is that a massive reduction in mtDNA content during early oogenesis leads to the bottleneck. To test this we estimated the mtDNA copy single exhibited consistent and moderate mtDNA copy numbers across developmental stages, while primary oocytes demonstrated substantial mtDNA expansion during early oocyte maturation. Some somatic cells possess a very low mtDNA copy number. We also demonstrated that PGCs have more than 100 mitochondria per cell. Taken together, we conclude that the mitochondrial bottleneck is not generated due to a mtDNA copy number drastic decline in early oogenesis rather to a small effective number of segregation units for mtDNA in mouse germ cells. Some somatic cell lineages have a narrow bottleneck during early differentiation. These results provide new information for generating mtDNA segregation models and for understanding of recurrence risks for mtDNA diseases. Less
|
