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。我们小组在当前资金周期中的工作表明，层粘连蛋白-10在头发和皮肤的附属物形态形成中起着至关重要的作用。我们发现，层粘连蛋白-10通过与其受体(1整合素)结合，导致sonic hedgehog(SHH)的表达，从而启动毛发胚芽的伸长和随后的毛发发育步骤。值得注意的是，我们发现外源层粘连蛋白-10挽救了lama5/-小鼠皮肤中毛发的形成，但执行这一功能的层粘连蛋白-10的结构域以及层粘连蛋白-10调节SHH表达的机制尚不清楚。为了定位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，以及截短和嵌合层粘连蛋白三聚体，以了解它们在lama5/-小鼠皮肤中拯救毛发发育的能力。这项建议还试图阐明层粘连蛋白-10在毛囊发育中的功能作用。为此，我们将研究层粘连蛋白-10对早期毛发标志物表达的影响，重点关注SHH表达的潜在上游调节因子。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。这一建议集中在层粘连蛋白-5的两个结构域，其中一个是从α3链加工而来的区域，G4-5结构域，我们已经证明它在肿瘤侵袭中发挥关键作用。另一个是β3短臂，它可能通过与III型胶原和层粘连蛋白-6相互作用，在将层粘连蛋白-5稳定到基底膜上发挥重要作用。我们试图阐明G4-5结构域的功能，并定位G4-5结构域的SCC促进区，评估G4-5结构域作为癌症治疗的潜在分子靶点。我们还试图描述层粘连蛋白Beta3短臂与其可能的配体、II型胶原和层粘连蛋白-6之间的相互作用，并研究其在真皮-表皮凝聚力和肿瘤发生中的作用。

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.