Laminins in the Skin

皮肤中的层粘连蛋白

• 批准号: 7867982
• 负责人: Matt Peter Marinkovich
• 金额: $ 35.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867982
• 关键词: Address; Binding; Biological Assay; C-terminal; Cells; Cilia; Data; Defect; Dermal; Dermatologic; Development; Disease; Drug or chemical Tissue Distribution; Epidermis; Epithelial; Epithelium; Event; Funding; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Hair; Hair follicle structure; Human; Immune; Immune system; Immunologics; Immunoproliferative Disorders; Infiltration; Inflammatory; Integrin Binding; Integrin Signaling Pathway; Integrins; Laminin; Measures; Mediating; Mesenchymal; Modeling; Molecular; Molecular Profiling; Morphogenesis; Mus; PDGFRB gene; PTK2 gene; Pathology; Pathway interactions; Peptide Signal Sequences; Phenotype; Point Mutation; Process; Production; Psoriasis; Role; Signal Transduction; Skin; Specificity; Staging; System; T-Lymphocyte Subsets; Testing; Transgenic Mice; United States; Work; Wound Healing; appendage; cytokine; human disease; in vivo; interleukin 20; interleukin-22; keratinocyte; mutant; overexpression; public health relevance; response; skin disorder; tongue papilla; tool

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.

描述（由申请人提供）：层粘连蛋白介导涉及细胞-基质相互作用的多种重要过程，并显示出组织分布和功能的显著多样性。我们小组在目前的支持周期中的工作暗示了层粘连蛋白-511在皮肤中的毛发和附属物形态发生中的重要作用。我们已经表明，层粘连蛋白-511是一种上皮衍生的分子，存在于毛发发育的最早阶段，作用于毛乳头（DP），使其在毛囊伸长期间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DP中初级纤毛发育和头蛋白表达，但该过程的细节仍知之甚少。本申请的第一个目的是鉴定和进一步描述DP成熟期间层粘连蛋白-整联蛋白结合和头蛋白表达之间发生的事件序列。为此，我们将测试我们的假设，即1321整联蛋白，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，促进初级纤毛形成，最终导致头蛋白表达和毛发发育。本申请的第二个目的是解决表皮免疫增殖，这是美国的主要皮肤病学问题。创伤愈合过程中层粘连蛋白-整合素结合促进GTCRac 1的活化，并与受控的表皮增殖相关。然而，我们已经表明，在转基因小鼠基底表皮中Rac 1的激活突变体的过表达产生与人类疾病银屑病具有许多相似性的不受控制的和免疫依赖性的表皮增殖。我们假设表皮Rac 1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Stat 3激活放大对免疫源性生长因子的增殖反应。在更充分地表征了该模型的免疫表型以及细胞因子表达谱之后，我们将解剖炎症和增殖途径，并确定诱导免疫增殖性疾病的细胞触发因子。这些研究将在分子水平上提供对产生免疫增殖性疾病病理学的角质形成细胞-免疫细胞相互作用的更精确的理解，最终导致开发更特异性和毒性更小的治疗方法。公共卫生关系：从这一支持周期中获得的进展使我们对层粘连蛋白如何控制毛发发育过程中上皮间质相互作用的理解取得了进展。第一个目标中的拟议研究将确定毛发形成早期事件中发生的事件顺序。本申请还提供了类似于人类疾病银屑病的非常有希望的免疫增殖性皮肤病模型的初步数据。第二个目标中提出的研究将确定细胞和分子相互作用，以及在该模型中沉淀表皮增殖和免疫浸润的触发因素。