Melanin in the skin protects the epidermis and the underlying dermis from the deleterious effects of ultraviolet radiation in the sun light. Therefore melanocyte homeostasis is essential for a functional epidermal melanin unit and healthy skin. Disruption of melanocyte homeostasis leads to skin disorders. Most notably, loss due to death of melanocyte causes depigmentary disorder vitiligo and accompanying skin photosensitivity, and gain of melanocytes due to unregulated proliferation as occurs in cutaneous melanoma could eventually lead to death. Exposure of intracellular proteins following death of normal and/or malignant melanocytes leads to break in tolerance and immune response to several melanosomal self antigens in vitiligo and melanoma. Therefore, understanding the mechanisms that regulate melanocyte homeostasis, specifically melanocyte death, is important for developing strategies to prevent and treat melanocytic disorders. While melanocyte death due to necrosis and apoptosis has been well investigated, mechanisms of autophagic death of melanocytes and the role of autophagy in the behavior of malignant melanocytes are not well understood. For example, it is not known whether a) susceptibility to develop cutaneous melanoma is related to ability to activate or inhibit autophagy upon oncogenic transformation of melanocytes, b) differences exist in activation of autophagy and autophagic cell death between melanocytes in darker and lighter skin individuals, and c) differences in activation of autophagy can account for susceptibility of resistance of melanocytes to malignant transformation. Autophagy, which normally serves as cell survival mechanism when cells are under stress, is regulated by mammalian Target of Rapamycin (mTOR) signaling pathway that responds to nutrient deprivation and other cell survival signals. Inhibition of mTOR signaling by rapamycin induces autophagy, which can be monitored by morphological (light microscopic immunofluorescence and electron microscopy) and biochemical methods. In our preliminary studies, we found that melanocytes from European and African ancestry show differential sensitivity to mTOR and autophagic cell death can be induced in malignant melanocytes by hyperactivation of oncogene BRAF. We hypothesized that autophagy plays a role in homeostasis of epidermal melanin unit. Here, we propose to address the following questions: Is autophagic cell death a normal homeostatic mechanism that maintains epidermal melanin unit? What role do keratinocytes play in sensitivity of melanocytes to autophagy? What is the role of Atg5 and Atg7 in sensitivity of melanocytes to mTOR inhibition? Experiments proposed here are expected to generate new scientific knowledge that could lead to better understanding of the pathogenesis of melanocytic disorders and may eventually lead to more effective treatments.
Pigment producing cells in the skin are maintained in equilibrium with respect to the surrounding keratinocytes to which they export melanin pigment that provides protection from damaging ultraviolet radiation in the sun light. However, if melanocytes undergo unscheduled cell death or fail to die when damaged, it can lead to skin diseases such as vitiligo and skin cancer melanoma. The aim of this proposal to investigate melanocyte cell death mechanism that scontribute to melanocytic disorders.
|Qiu, Lei; Song, Zhiqi; Setaluri, Vijayasaradhi (2014) Oxidative stress and vitiligo: the Nrf2-ARE signaling connection. J Invest Dermatol 134:2074-6|