Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Cytotoxic Mechanisms in Cutaneous Disease

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The major objective of this grant over the past 20 years has been to study key aspects of the mechanisms of immunologic cytotoxicity in skin disease. The major focus has been on cytotoxicity to melanocytes and keratinocytes in diseases such as vitiligo and lupus erythematosus. The purpose of this COMPETITIVE RENEWAL is to characterize the mechanisms of Fas-mediated cytotoxicity in melanocytes and basal keratinocytes, especially in situations where the normal resistance of these cells is overcome. This grant will emphasize studies to identify the anti-apoptotic defenses of these cells, and to characterize the signaling pathways that maintain these defenses. This proposal addresses the molecular and cellular biology of a fundamental characteristic of the cells of the basal layer of the epidermis: their intrinsic resistance to immunologic cytotoxicity, especially Fas-mediated apoptosis: Specific Aim 1 : To confirm that both melanocytes and proliferating keratinocytes are Fas Type II cells, requiring both extrinsic and intrinsic pathways for Fas-mediated apoptosis. Specific Aim 2, 3 and 4: To demonstrate the importance of PI3K/Akt, NF-kB, and Ras pathways in control of the susceptibility of melanocytes and keratinocytes to Fas-mediated apoptosis, and identify the anti-apoptotic targets involved in extrinsic and/or intrinsic pathways for Fas-mediated apoptosis. Specific Aim 2: For the PI3K/Akt pathway. Specific Aim 3: For the NF-kB pathway. Specific Aim 4: For the Ras pathway. Specific Aim 5: To identify unanticipated anti-apoptotic targets of PI3K, NF-kB, and Ras for Fas mediated apoptosis in melanocytes and basal keratinocytes using proteomic analysis. In summary, we will demonstrate that melanocytes and keratinocytes require the intrinsic pathway for Fas-mediated apoptosis (aim 1), and we will determine whether and how PI3K/Akt, NF-kB, and Ras control the resistance of melanocytes and keratinocytes to Fas-mediated apoptosis (aim 2, 3, and 4). In addition, we will identify unanticipated targets for these signal pathways that contribute to anti-apoptotic defenses in these cells (aim 5).

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