This is a request for an additional five years of funding for """"""""Cytotoxic Mechanisms in Cutaneous Disease"""""""" which has been funded to sixteen years to study the mechanisms of immunologic damage to keratinocytes and melanocytes, a central component in important skin diseases such as photosensitive lupus erythematosus, vitiligo, erythema multiforme, toxic epidermal necrolysis and lichen planus. We have found that the epidermis is intrinsically resistant to immunologic cytotoxicity, due in large part to resistance of basal keratinocytes and melanocytes to apoptosis induced by immunologic triggers. We hypothesize that this resistance to apoptosis in undifferentiated keratinocytes and melanocytes is maintained by """"""""survival"""""""" signals provided by growth factor activation of receptors and by extracellular matrix activating cell surface integrins. We propose to test the effect of growth factor and integrin blockade on the susceptibility of melanocytes and keratinocytes to induction of apoptosis by ultraviolet radiation (UVR), ionophore, anti-Fas, and cytokines. Using combinations of blocking, rescue and transfection experiments, we will verify that survival signals in melanocytes and keratinocytes are transmitted through ras activation, and directly regulate expression of important proteins which control apoptosis, such as bc1-2, and perhaps bc1-x, Bax and Bad. We will also study regulation of these important proteins following nuclear translocation of p53, and important trigger of apoptosis induced by UVR. This proposal addresses the molecular and cellular biology of a fundamental characteristic of the basal layer of the epidermis: its intrinsic resistance to immunologic cytotoxicity. Although these anti- apoptotic defenses protect the skin from unwanted effects of inflammation, they may also allow favor survival melanoma and squamous cell carcinoma.
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