Laminins mediate a variety of important processes involving cell-matrix interactions and show a remarkable diversity of tissue distribution and function. Work by our group during the current funding cycle implicates an essential role for laminin-511 in hair and appendage morphogenesis in the skin. We have shown that laminin-511 is an epithelial derived molecule, present at the earliest stages of hair development, which acts upon the dermal papilla (DP), allowing it to properly respond to the follicular epithelium during hair follicle elongation. Laminin-511 interacts with ?1 integrin to effect signaling changes leading to primary cilia development and noggin expression in the DP, however the details of this process remain poorly understood.
The first Aim of the current proposal seeks to identify and further delineate the sequence of events which take place between laminin-integrin binding and noggin expression during DP maturation. Towards this end we will test our hypothesis that ?3?1 integrin, through laminin-511 binding, promotes a sequence of events including FAK, ILK and PDGFR activation which promote primary cilia formation ultimately leading to noggin expression and hair development.
The second Aim of this proposal addresses epidermal immuno-proliferation, a major dermatologic problem in the United States. Laminin-integrin binding during wound healing promotes activation of the GTPase Rac1 and is associated with a controlled epidermal proliferation. However, we have shown that overexpression of an activated mutant of Rac1 in transgenic mouse basal epidermis produces an uncontrolled and immune dependent epidermal proliferation with many similarities to the human disease psoriasis. We hypothesize that epidermal Rac1 activation promotes interaction with the immune system through the production of inflammatory cytokines, and amplifies the proliferative response to immune derived growth factors by facilitating Stat3 activation. After more fully characterizing the immunologic phenotype as well as the cytokine expression profile of this model, we will dissect inflammatory and proliferative pathways and determine the cellular triggering factors that induce immunoproliferative disease. These studies will provide a more precise understanding, on a molecular level, of the keratinocyte-immunocyte interactions which produce immuno-proliferative disease pathology, ultimately leading to the development of more specific and less toxic therapies.
SUMMARY Advances derived from this funding cycle have led to advances in our understanding of how laminins control epithelial mesenchymal interactions during hair development. The proposed studies in the first Aim will determine the sequence of events which occur in the early events of hair formation. This proposal also presents preliminary data of a highly promising model of immunoproliferative skin disease resembling the human disease psoriasis. The studies proposed in the second Aim will determine the cellular and molecular interactions, as well as the triggering factors which precipitate epidermal proliferation and immune infiltration in this model.
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|Winge, MÃ¥rten C G; Ohyama, Bungo; Dey, Clara N et al. (2016) RAC1 activation drives pathologic interactions between the epidermis and immune cells. J Clin Invest 126:2661-77|
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|Sakai, Noriyasu; Waterman, Elizabeth A; Nguyen, Ngon T et al. (2010) Observations of skin grafts derived from keratinocytes expressing selectively engineered mutant laminin-332 molecules. J Invest Dermatol 130:2147-50|
|DeRouen, Mindy C; Zhen, Hanson; Tan, Si Hui et al. (2010) Laminin-511 and integrin beta-1 in hair follicle development and basal cell carcinoma formation. BMC Dev Biol 10:112|
|Nguyen, Bichchau; Dusek, Rachel L; Beaudry, Veronica G et al. (2009) Loss of the desmosomal protein perp enhances the phenotypic effects of pemphigus vulgaris autoantibodies. J Invest Dermatol 129:1710-8|
|Gao, Jing; DeRouen, Mindy C; Chen, Chih-Hsin et al. (2008) Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis. Genes Dev 22:2111-24|
|Liu, Zhi; Sui, Wen; Zhao, Minglang et al. (2008) Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J Autoimmun 31:331-8|
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