The long term goal of this proposal is to foster the development in five years of a productive, scientist performing independent research on the genetics of vertebrate skin development. Loss of or abnormal regulation of integument function may result in hypovolemia, infection, or skin cancer. To develop appropriate therapies for abnormal skin, it is crucial to know the fundamental mechanisms in the normal development of skin and its appendages. Recent studies of key regulatory molecules controlling development of hair follicle provide new opportunities to advance our understanding of hair and skin development. One set of such molecules is the vertebrate homologs of the Drosophila segment polarity genes. Recent studies suggest genes involved in the Sonic hedgehog (Shh) I patched (ptc) signaling system are conserved at many levels. Our working hypothesis from preliminary data is that Shh I ptc are involved in inducing follicular differentiation and in proximal-distal and anterior -posterior patterning of the follicle.
We aim to examine Shh and ptc expression during normal skin development and regenerating vibrissae to make predictions regarding function. We will use standard in situ hybridization techniques and compare expression to other know regulators in the follicle such as Msx-1, LEF-1, BMP-2, and Hox C-6. We will analyze ptc/Shh phenotypes using constructed mouse mutants.
We aim to generate epidermal-specific ectopic expression of ptc and Shh, loss of function ptc alleles using homologous recombination in embryonic stem cells, and mosaic skin expression of ptc using the Cre-lox recombination system. These experiments should provide models of the complex intercellular signaling process in the skin. The proposal will provide the candidate with rigorous training in mouse genetics and developmental biology through a combination of coursework, seminars, and supervised research in the first two years and supervised research in later years. This training is crucial in the transition to an independent investigator with the tools required to study the basic molecular mechanisms of skin development and regeneration.
