STUDY OF MICE IN WHICH THE TGF BETA GENE HAS BEEN DISRUPTED

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Of the three TGF-b isoforms, type 1 TGF-b is both the most abundant in most tissues and the most acutely regulated in injury, repair, and in disease pathogenesis. Although they lack any obvious developmental defects, mice in which the TGF-b1 gene has been knocked out by targeted disruption die at about 3 weeks of age of multifocal inflammatory disease. Immunosuppressive treatments including rapamycin, dexamethasone, anti-CD4, and anti-CD8 can prolong the life of the TGF-b1 null mice. This has enabled study of wound healing in 4-5 week old mice in which maternally- transferred TGF-b1 has been depleted. Despite the prominent role of TGF-b1 in wound healing, there is no delay in closure of incisional wounds of TGF-b1 null mice. However, the rate of formation and amount of granulation tissue and collagen deposition is reduced compared to wildtype littermates and scarring is also reduced. The data show that release of TGF-b1 from platelets is not essential to initiation of tissue repair and suggest that compensatory mechanisms, possibly involving other cytokines or other TGF-b isoforms, may overcome the effects of loss of TGF-b1 in null mice. Other studies in the TGF-b1 null mice have shown suppressed expression of the mRNAs for several mitochondrially encoded components of the electron-transport chain, consistent with ultrastructural abnormalities in Golgi and mitochondria of cells of liver, heart, and lung of TGF-b1 null mice suggestive of an energy deficit and impaired vesicular transport. Functional studies have shown that whereas maximal capacity of individual electron chain components is not altered in the null mice, there is a significant decrease in the oxidative capacity of heart tissue. Moreover, studies with hepatocyte cell lines derived from these mice show that null cells have less than 25% the oxidative rate of wildtype cells. Treatment of either null or wildtype cells with TGF-b in vitro results in rapid upregulation of expression of mitochondrial genes. It is yet to be determined whether such treatment will reverse the deficit in oxidative metabolism. Present investigations are aimed at determining the mechanism whereby TGF-b1 regulates cellular energetics and expression of mitochondrial genes.