学位論文 Study of genetic background-dependent diversity of renal failure caused by the tensin2 gene deficiency in the mouse [an abstract of entire text]

佐々木, 隼人

2015-03-25
内容記述
Tns2 is thought to be a component of the cytoskeletal structures linking actin filaments with focal adhesions and plays a role as an intracellular signal transduction mediator through integrin in podocytes, and how it functions is unclear. Tns2-null mutation (Tns2nph) leads to massive albuminuria following podocyte foot process effacement in ICGN mice, the origin of the mutation, and D2 mice, but not in B6 mice and 129T mice. Elucidating the reasons for these differences in diverse genetic backgrounds could help unraveling Tns2 function in podocytes. The author produced the congenic mouse in which Tns2nph is introgressed into FVB background (FVB- Tns2nph), and evaluated the progression of kidney disease. FVB-Tns2nph mice developed albuminuria, renal fibrosis and renal anemia, like ICGN mice. In FVB-Tns2nph mice, podocyte foot process effacement was observed with an electron microscope at as early as 4 weeks of age. This revealed that FVB strain is susceptible to Tns2-deficiency. Then, two resistant strains (B6 and 129T) and three susceptible strains (D2, FVB and ICGN or ICGN(-)) were subjected to comparative analyses to elucidate the reasons for the difference in susceptibility to Tns2-deficiency. Comparative analysis of glomerular gene expression identified H2-Q5, major MHC-I antigen canonical splice variant, that was expressed in the susceptible strains at level >2-fold lower than in the resistant strains. Comparative analysis of nsSNP revealed 4 candidate genes associated with Tns2nph-induced nephropathy, Kif26a, Nes, Btla and Sh3bp1. Among them, mouse Kif26a missense variant T690I lies within a kinesin motor domain, and the corresponding amino acid residue of KIF26A is highly conserved among other animals including humans.
Hokkaido University(北海道大学). 博士(獣医学)
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http://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/59316/1/Hayato_Sasaki_summary.pdf

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