Laminins in the Skin

皮肤中的层粘连蛋白

• 批准号: 6825113
• 负责人: Matt Peter Marinkovich
• 金额: $ 35.25万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825113
• 关键词: SCID mouse; antibody; antiserum; athymic mouse; biological signal transduction; cell migration; clinical research; extracellular matrix; gene expression; genetically modified animals; hair follicle; human tissue; keratinization; keratinocyte; laminin; neoplastic process; protein localization; protein protein interaction; protein structure function; recombinant proteins; squamous cell carcinoma; transcription factor

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 funding cycle implicates an essential role for laminin-10 in hair and appendage morphogenesis in the skin. We found that laminin-10 through binding with its receptor, (1 integrin, led to the expression of sonic hedgehog (SHH) to initiate the elongation of hair germs and subsequent steps in hair development. Remarkably, we found that exogenous laminin-10 rescued hair formation in lama5-/- mouse skin, however the domains of laminin-10 which perform this function and the mechanism of regulation of SHH expression by laminin-10 remains unclear. To localize the residues on laminin-10 which mediate hair development, we propose to test exogenous laminin G domains, as well as truncated and chimeric laminin trimers for their ability to rescue hair development in lama5-/- mouse skin. This proposal also seeks to elucidate the functional role of laminin-10 in hair follicle development. To this end, we will examine the effects of laminin-10 on the expression of early hair markers, focusing on potential upstream regulators of SHH expression. Other work from our group during the current cycle demonstrates that laminin-5 is required for squamous cell carcinoma (SCC) development. This proposal focuses on two domains of laminin-5, one of which is the region processed from the alpha3 chain, the G4-5 domain, which we have shown plays a critical role in carcinoma invasion. The other is the beta3 short arm, which may play an important role in stabilizing laminin-5 to the basement membrane, through interaction with type VII collagen and laminin-6. We seek to elucidate the function and localize the SCC promoting region of the G4-5 domain, evaluating the G4-5 domain as a potential molecular target for cancer therapy. We also seek to characterize the interactions between the laminin beta3 short arm with its putative ligands, type VII collagen and laminin-6, and examine its role in dermal-epidermal cohesion and carcinoma development.

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着多样性。 我们小组在当前资助周期内的工作表明，层粘连蛋白 10 在皮肤毛发和附属物形态发生中发挥着重要作用。 我们发现，层粘连蛋白-10通过与其受体（1整合素）结合，导致声刺猬（SHH）的表达，从而启动毛胚的伸长和头发发育的后续步骤。值得注意的是，我们发现外源性层粘连蛋白-10拯救了lama5-/- 小鼠皮肤中毛发的形成，然而执行此功能的层粘连蛋白 10 的结构域以及层粘连蛋白 10 调节 SHH 表达的机制仍不清楚。为了了解介导毛发发育的层粘连蛋白 10 上的残基，我们建议测试外源层粘连蛋白 G 结构域以及截短的嵌合层粘连蛋白三聚体，以了解其拯救 lama5-/- 小鼠皮肤毛发发育的能力。 laminin-10 在毛囊发育中的功能作用 为此，我们将研究 laminin-10 对早期毛发标记物表达的影响，重点关注潜在的上游调节因子。我们小组在当前周期中的其他工作表明，层粘连蛋白 5 是鳞状细胞癌 (SCC) 发展所必需的。 该提案重点关注层粘连蛋白-5 的两个结构域，其中之一是由 alpha3 链加工而成的区域，即 G4-5 结构域，我们已经证明该结构域在癌症侵袭中发挥着关键作用。 另一个是 beta3 短臂，它可能通过与 VII 型胶原和层粘连蛋白 6 相互作用，在将层粘连蛋白 5 稳定到基底膜方面发挥重要作用。 我们试图阐明 G4-5 结构域的功能并定位 SCC 促进区域，评估 G4-5 结构域作为癌症治疗的潜在分子靶点。 我们还试图表征层粘连蛋白 beta3 短臂与其假定配体、VII 型胶原和层粘连蛋白 6 之间的相互作用，并检查其在真皮-表皮凝聚力和癌症发展中的作用。