Laminins in the Skin

描述(申请人提供)：层粘连蛋白调节涉及细胞-基质相互作用的各种重要过程，并显示出组织分布和功能的显着多样性。我们小组在当前支持周期中的工作表明，层粘连蛋白-511在头发和皮肤的附属物形态发生中起着至关重要的作用。我们已经证明，层粘连蛋白-511是一种上皮源性分子，存在于毛发发育的最早阶段，作用于毛乳头(DP)，使其在毛囊伸长过程中对毛囊上皮做出适当的反应。层粘连蛋白-511与21整合素相互作用，影响信号变化，导致初级纤毛发育和dp中noggin的表达，但这一过程的细节仍不清楚。本申请的第一个目的是鉴定和进一步描绘在DP成熟过程中在层粘连蛋白-整合素结合和noggin表达之间发生的事件序列。为此，我们将检验我们的假设，即1321整合素通过层粘连蛋白-511结合，促进包括FAK、ILK和PDGFR激活在内的一系列事件，这些事件促进初级纤毛形成，最终导致noggin表达和毛发发育。这项应用的第二个目的是解决表皮免疫增殖，这是美国的一个主要皮肤病问题。在伤口愈合过程中，层粘连蛋白-整合素结合促进GTPase rac1的激活，并与受控的表皮增殖有关。然而，我们已经证明，在转基因小鼠的基底表皮中过表达一个激活的rac1突变体会产生一种不受控制的、免疫依赖性的表皮增殖，这与人类银屑病有许多相似之处。我们假设，表皮rac1的激活通过产生炎性细胞因子来促进与免疫系统的相互作用，并通过促进STAT3的激活来放大对免疫衍生生长因子的增殖反应。在更全面地描述了该模型的免疫表型和细胞因子表达谱后，我们将剖析炎症和增殖途径，并确定导致免疫增殖性疾病的细胞触发因素。这些研究将在分子水平上提供对角质形成细胞-免疫细胞相互作用的更准确理解，这些相互作用产生免疫增殖性疾病的病理，最终导致更特异和毒性较低的治疗方法的开发。与公共健康相关：从这个支持周期中获得的进展导致了我们对层粘连蛋白如何在头发发育过程中控制上皮间充质相互作用的理解上的进步。第一个目的的拟议研究将确定在毛发形成的早期事件中发生的事件的顺序。这项申请还提供了一种非常有希望的免疫增殖性皮肤病模型的初步数据，该模型类似于人类牛皮癣。第二个目标中提出的研究将确定该模型中细胞和分子的相互作用，以及促使表皮增殖和免疫渗透的触发因素。

DESCRIPTION (provided by applicant): 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 support 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 21 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 application 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 1321 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 application 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. PUBLIC HEALTH RELEVANCE: Advances derived from this support 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 application 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.