Research in my laboratory has been focused on studying the functions of TGFß (transforming growth factor ß) signaling in carcinogenesis, wound healing, skin/appendage development and diseases. TGFß is a multifunctional cytokine that is crucial for the maintenance of epithelial homeostasis. We have developed several inducible and epithelial-specific transgenic/knockout mouse models (gene-switch) that allow examination of the functions of TGFß signaling components at specific stages during carcinogenesis, wound healing, and skin/appendage development. Another unique feature of these transgenic/knockout mouse models is that they allow identification of downstream targets of TGFß signaling by acute gene induction/ablation, which may be difficult to be distinguished from a secondary effect in the conventional transgenic/knockout mouse models. Ongoing research projects are as follows:

1) Role of TGFß in carcinogenesis – Alterations in the TGFß signal transduction pathway at any level, i.e., the ligand, receptor, and signaling mediator (e.g., Smads), lead to a higher susceptibility to cancer. We will induce TGFß1 expression or delete the TGFß receptor in the discrete stages of initiation, promotion and malignant conversion during carcinogenesis in the skin and head and neck epithelia. These experiments allow us to precisely determine the roles of TGFß in different stages of skin carcinogenesis and to analyze the underlying molecular mechanisms of TGFß functions in carcinogenesis.

2) The functions of Smads in carcinogenesis – Smad family members not only mediate TGFß signaling, but are also suggested to be tumor suppressors. Mutations of Smads have been identified in various human cancers, suggesting that loss of Smads may also lead tumor cells to develop resistance to TGFß-induced growth inhibition. We have found that loss of Smads correlates with malignant conversion during skin carcinogenesis. To precisely determine the stage-specific functions of Smads in carcinogenesis, we will use inducible and epithelial-specific knockout mice, in which individual Smad genes can be ablated at certain stages of carcinogenesis in the skin and head and neck epithelia.

3) The functions of Smads in skin development – The signaling pathways of the TGFß superfamily are among the most important mechanisms in epidermal development. We have generated Smad7 (an anti-Smad) transgenic mice. These transgenic mice exhibited severe developmental defects in hair follicles and several epithelial tissues, and died shortly after birth. We will develop inducible and epidermal-specific Smad7 transgenic mice to further study the mechanisms of pathological functions of Smad7. Since Smad7 blocks signal transduction of both TGFß and BMP pathways, to further dissect which pathway is mainly involved, we will delete individual Smads in the epidermis, which are either TGFß-specific or BMP-specific. Changes in the development of the epidermis and its appendages will be analyzed in these mouse models. In addition, Smad responsive genes can be identified from the screening of differentially expressed genes after the acute induction of expression or deletion of Smads in the epidermis and hair follicles.

4) Role of TGFß signaling in wound healing – TGFß1 has both positive and negative effects on wound healing at all stages. In addition, our preliminary data have shown that overexpression of Smad7 in keratinocytes resulted in accelerated wound healing. Thus, Smad7 overexpression may selectively block the negative effects of TGFß1 on wound healing, such as inhibition of reepithelialization and excessive inflammation. We will utilize inducible and epidermal specific (gene-switch) transgenic mouse models, which allow us to induce expression of TGFß1 and/or Smad7 at different levels and during one or more following stages of wound healing: inflammation, reepithelialization, granulation tissue formation, wound contraction and tissue remodeling. Wounds excised from the above stages will be used to analyze the stage-specific effects of TGFß1 and Smad7 on wound healing and to identify their transcriptional targets.

5) The pathological functions of TGFß1 in inflammatory skin disorders – We have recently generated transgenic mice which overexpress the latent form of TGFß1 in the epidermis and hair follicles. Different from the active form of TGFß1 which exhibits a potent growth inhibitory effect in the epidermis, the latent form of TGFß1 elicited significant inflammation in the skin, which mimics psoriasis. We will study how and where the latent TGFß1 is activated in the skin and the molecular basis of TGFß1-induced inflammatory disorders.