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• W13532557 abstract "The 5' stem-loop (5'SL) in the 5' UTR of collagen α1(I) and α2(I) mRNAs is the key element regulating stability and translation of collagen mRNAs. LARP6 is the RNA binding protein which exhibits high affinity binding to the 5'SL of collagen α1(I) and α2(I) mRNAs. In the first part of the dissertation, we report that vimentin filaments associate with type I collagen mRNAs in a 5'SL and LARP6 dependent manner. This association is needed for stabilization of type I collagen mRNAs. Our conclusion was based on the following lines of evidence. First, RNA immunoprecipitation and cellular fractionation experiments showed that collagen α1(I) and α2(I) mRNAs exhibit specific interaction with vimentin intermediate filaments. This was substantiated by RNA-FISH experiments which showed that collagen I mRNAs colocalize with vimentin filaments. Second, we showed that the binding of collagen mRNAs to vimentin intermediate filaments is dependent on the 5' stem-loop. Collagen mRNAs from mouse embryonic fibroblasts carrying a knock-in mutation in the 5'SL failed to interact with vimentin intermediate filaments. Third, interaction of collagen mRNAs with collagen mRNAs was mediated by the RNA binding protein, LARP6, which specifically binds the 5'SL of type I collagen mRNAs. siRNA knock down of LARP6 abrogated the interaction of type I collagen mRNAs with vimentin intermediate filaments. We also found that LARP6 interacts and colocalizes with vimentin intermediate filaments. Mapping of the domain of LARP6 needed for interaction with vimentin revealed that the La domain of LARP6 is necessary and sufficient to interact with viemntin. Fourth, disruption of vimentin filaments using the vimentin disrupting drug β,β'-imminodipropionitrile or by expressing a dominant negative intermediate filament markedly reduced production of type I collagen. The reduction in collagen synthesis was due to decreased stability of collagen mRNAs. Last, but not least, we observed a marked reduction in collagen synthesis from vimentin -/- mouse fibroblasts. This reduced collagen production was also due to reduced stability of type I collagen mRNAs in vimentin deficient fibroblasts. This was consistent with the impaired wound healing phenotype displayed by vimentin deficient mice further verifying the important role of vimentin filaments in collagen synthesis. We concluded that vimentin intermediate filaments play a key role in the development of tissue fibrosis by stabilizing type I collagen mRNAs. This finding served as a basis for targeting vimentin in the investigation of a novel anti-fibrotic therapy. In the second part of the project, we examined the antifibrotic effects of Withaferin-A. The intermediate filament vimentin is the primary target of Withaferin-A. In light of our finding of the role of vimentin in stabilizing collagen mRNAs, we hypothesized that Withaferin A may reduce collagen production by disrupting vimentin filaments and decreasing the stability of collagen mRNAs. We thus aimed to determine if Withafrein-A exhibits anti-fibrotic properties in…" @default.
• W13532557 created "2016-06-24" @default.
• W13532557 creator A5044851130 @default.
• W13532557 date "2011-01-01" @default.
• W13532557 modified "2023-09-26" @default.
• W13532557 title "Understanding the functions of vimentin filaments in collagen expression and targeting vimentin filaments for the treatment of fibrosis" @default.
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