The research in the Gudas laboratory is focused on the development of new drugs for cancer prevention and cancer treatment. We are also using pharmacological approaches to enhance regenerative processes/tissue regrowth after injury. Much of our research deals with retinoids. Retinoids, which include both natural and synthetic derivatives of vitamin A (retinol), control many aspects of normal cell differentiation and influence the process of carcinogenesis. Retinoids also have profound effects on amphibian limb regeneration. Retinoids are used clinically in the treatment of a number of diseases, including cancer, and skin conditions such as acne and psoriasis. The responses of many cell types to retinoid treatment are mediated initially by intracellular retinoid receptors and involve changes in cell proliferation and cell differentiation. The Gudas laboratory is studying how retinoids elicit these dramatic changes in cells through the identification and analysis of the genes which are regulated by retinoids. These genes include Rex1, a stem cell marker and transcription factor which is transcriptionally repressed by retinoids, and homeobox genes, which encode transcription factors important in embryonic cell differentiation. We have identified retinoic acid responsive "enhancers," or DNA control regions, 3' of homeobox genes called Hoxa-1 and Hoxb-1. We have shown that these enhancers activate transcription of these Hox genes in response to retinoic acid both in cultured cells and in transgenic mice. Murine embryonic stem cells differentiate in response to retinoids, and we are analyzing how this differentiation response is controlled.

Other research interests of the Gudas laboratory include the analysis of the expression and functions of the intracellular retinoid binding proteins CRABP-I and CRABP-II; the study of the effects of the cyclic AMP signaling system on retinoid regulated genes; the analysis of various retinoid analogs in the treatment of human oral squamous cell carcinomas (epithelial tumors of the head and neck), prostate, breast, renal, and bladder carcinomas; the identification of new retinol (vitamin A) metabolites in specific cell types such as epithelial and neuronal cells; and the use of LRAT (lecithin:retinol acyltransferase), an enzyme which esterifies retinol, as a molecular marker to identify normal vs. malignant cells in humans. We have recently developed an improved model of mouse oral cavity carcinogenesis and are using this model system to test new therapies employing retinoids plus histone deacetylase inhibitors. These therapies are also being tested in kidney, bladder, and prostate cancer patients in clinical trials conducted at Weill Cornell. Collectively, these research projects should lead to new insights into the roles of retinoids in the regulation of cell growth and differentiation and to improved therapies for diseases such as cancer.

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