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。在当前的资助周期中，我们小组的工作暗示了层粘连蛋白-10在头发和皮肤附属物形态发生中的重要作用。我们发现，laminin-10通过与其受体（1整合素）结合，导致sonic hedgehog （SHH）的表达，从而启动毛发细菌的伸长和毛发发育的后续步骤。值得注意的是，我们发现外源性lamin10可以挽救lama5-/-小鼠皮肤的毛发形成，然而lamin10执行这一功能的结构域以及lamin10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，以及截断和嵌合层粘连蛋白三聚体在lama5-/-小鼠皮肤中挽救毛发发育的能力。本研究也试图阐明层粘连蛋白-10在毛囊发育中的功能作用。为此，我们将研究层粘胶蛋白-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。本研究主要关注laminin-5的两个结构域，其中一个是由alpha3链加工的区域，即G4-5结构域，我们已经证明该结构域在肿瘤侵袭中起关键作用。另一个是β a3短臂，它可能通过与VII型胶原和laminin-6相互作用，在稳定laminin-5到基底膜上发挥重要作用。我们试图阐明G4-5结构域的功能和定位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β 3短臂与其假定的配体，VII型胶原和层粘连蛋白6之间的相互作用，并研究其在真皮-表皮内聚和癌发展中的作用。

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.