Altered TGF-beta activation in mouse heart development

New York University School Of Medicine, New York NY

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Abstract

Both transforming growth factor beta (TGF-beta) and latent TGF-beta binding protein (LTBP) play important roles in the development of the embryonic heart as proper signaling through the TGF-beta pathway is needed both for regulating cell proliferation and gene expression. However, cells secrete TGF-beta in a latent form bound to the LTBP as large latent complex (LLC). The release of TGF-beta from this complex is regulated by the activity of proteases. Our proposal consists of generating transgenic mice that express truncated form of TGF-beta binding region (CR3) of LTBP-1 under two heart specific promoters, for alpha-myelin heavy chain ands myelin light chain (alpha-MHC, MLC). In that way we will try to characterize the consequences of inappropriate activation of latent TGF-beta, as a result of disruption of its binding to LTBP, without affecting the expression of TGF-beta and LTBP. We will test the hypothesis that expression of CR3 will result in increased levels of active TGF-beta in the heart and it's consequences on heart development. We will monitor active TGF-beta in heart during prenatal and postnatal development. As a control of our hypothesis, experiments designed to counter the actions of excess TGF-beta in the heart will be performed. Those experiments will include incubation with TGF-beta neutralizing antibodies and LAP peptides. This should revert the phenotype toward the wild type situation. These experiments will enhance our understanding of TGF-beta function in early and late development of the mouse heart. We anticipate that these results will contribute to our understanding of the extra-cellular control of signaling molecules such as TGF-beta and the role of LTBP in that signaling.