Laminins in the Skin

描述（由申请人提供）：层粘连蛋白介导多种涉及细胞-基质相互作用的重要过程，并显示出显著的组织分布和功能多样性。我们小组在当前支持周期中的工作暗示了层粘连蛋白-511在头发和皮肤附属物形态发生中的重要作用。我们已经证明，层粘连蛋白-511是一种上皮衍生分子，存在于头发发育的早期阶段，它作用于真皮乳头（DP），使其在毛囊伸长期间对毛囊上皮作出适当的反应。Laminin-511与21整合素相互作用，影响DP中导致初级纤毛发育和noggin表达的信号变化，然而这一过程的细节尚不清楚。当前应用程序的第一个目的是确定并进一步描述在DP成熟过程中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，我们将验证我们的假设，即1321整合素通过层粘连蛋白511结合，促进一系列事件，包括FAK， ILK和PDGFR激活，从而促进初级纤毛的形成，最终导致noggin的表达和头发的发育。这个应用程序的第二个目的是解决表皮免疫增殖，一个主要的皮肤病问题在美国。在伤口愈合过程中，层粘连蛋白整合素的结合促进了GTPase Rac1的激活，并与控制表皮增殖有关。然而，我们已经证明，在转基因小鼠基底表皮中过度表达激活的Rac1突变体会产生不受控制的免疫依赖性表皮增殖，与人类疾病牛皮癣有许多相似之处。我们假设表皮Rac1激活通过产生炎性细胞因子促进与免疫系统的相互作用，并通过促进Stat3激活放大对免疫源性生长因子的增殖反应。在更全面地描述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，并确定诱导免疫增生性疾病的细胞触发因素。这些研究将在分子水平上对角化细胞-免疫细胞相互作用提供更精确的理解，这些相互作用产生免疫增殖性疾病病理，最终导致更特异性和毒性更小的治疗方法的发展。公共卫生相关性：从这种支持循环中获得的进展使我们对头发发育过程中层粘连蛋白如何控制上皮间充质相互作用的理解取得了进展。在第一个目标中提出的研究将确定在头发形成的早期事件中发生的事件的顺序。这个应用也提供了一个非常有前途的模型的免疫增生性皮肤疾病类似于人类疾病牛皮癣的初步数据。在第二个Aim中提出的研究将确定细胞和分子的相互作用，以及引发该模型中表皮增殖和免疫浸润的触发因素。

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.