Transforming growth factor β (TGFβ) and its family members are involved in many phases of liver disease development and iron regulation. We have identified unexplored players in liver disease and iron-related disorders: TGF signalling intermediates. In this project, we build on our exciting findings to examine the molecular mechanisms involved in TGF signalling intermediates-mediated disease progression and their potential as targets for liver and iron-related disease.
The overall aims of this study are to examine the expression of TGF signalling intermediates in the liver, to specifically deplete TGF signalling intermediates in liver cells and examine consequences on liver disease and iron-related disease markers, to generate liver cell-specific deletions in mice and examine consequences on liver disease and iron-related disease markers and to identify TGF signalling intermediates targeting molecules.
In the proposed research, we will identify the cellular roles of TGF signalling intermediates and their importance in the progression of liver disease and in iron regulation and will develop and test strategies to target TGF signalling intermediates preferentially in specific cell types of the liver. In this project, we are to examine the expression of these proteins in the specific cell-types of the liver and examine the consequences of depletion of these genes in vitro on markers of liver disease and iron metabolism. Liver cell-specific deletions of these proteins in mice will be generated. Lastly, we will use specific siRNAs identified to target these genes in vivo. All resources, animal models, equipment, and facilities required for the successful completion of the proposed research project are available including animal and cell culture facilities, microscopes, real-time PCR instruments, FACS, and histochemical facilities. Knockout mice and conditionally deleted mice are already breeding, and the murine models of liver disease are routinely used in the laboratory.
Expected outcomes will be the identification of the molecular mechanisms involved in TGF signalling intermediates-mediated disease progression and their potential as targets for liver and iron-related disease.