Laminins in the Skin

皮肤中的层粘连蛋白

• 批准号: 7227234
• 负责人: Matt Peter Marinkovich
• 金额: $ 33.43万
• 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/7227234
• 关键词: Adhesions; Antibodies; Basement membrane; Binding; Carcinoma; Cell-Matrix Junction; Cells; Collagen Type VII; Complementary DNA; Dermal; Development; Drug or chemical Tissue Distribution; Erinaceidae; Facility Construction Funding Category; Funding; Germ; Hair; Hair follicle structure; Immune Sera; Integrins; Laminin; Ligands; Localized; Mediating; Molecular; Molecular Target; Morphogenesis; Mus; Normal tissue morphology; Play; Process; Reagent; Recombinants; Regulation; Role; Skin; Skin Carcinoma; Squamous cell carcinoma; Tertiary Protein Structure; Testing; Upper arm; Work; appendage; cancer therapy; cohesion; disulfide bond; keratinocyte; laminin-10; laminin-5; laminin-6; migration; mutant; receptor; secretion process; tumor

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）：层粘连蛋白介导了涉及细胞矩阵相互作用的各种重要过程，并显示了组织分布和功能的显着多样性。 我们小组在当前的资金周期中的工作暗示了层粘连蛋白10在皮肤中的头发和附属形态发生中的重要作用。 我们发现层粘连蛋白10通过与其受体结合（1整联蛋白，导致Sonic刺猬（SHH）的表达启动头发细菌的伸长延伸，并在头发发育的后续步骤中伸长。值得注意的是，我们发现外源性层粘连蛋白-10救出了。 LAMA5 - / - 小鼠皮肤中的头发形成，但是层粘连蛋白10的结构域执行此功能，而laminin-10的调节机制尚不清楚，以介导层粘连蛋白10的残基提议测试外源性层粘连蛋白G结构域，以及截短和嵌合层粘连蛋白的三聚体，以挽救Lama5 - / - 小鼠皮肤的头发发育的能力这一末端，我们将检查层粘连蛋白10对早期头发标记的表达的影响，重点是在当前循环中我们组的其他作品的潜在上游调节剂。 SCC）开发。 该提案的重点是层粘连蛋白5的两个结构域，其中一个是从Alpha3链G4-5结构域处理的区域，我们显示的该区域在癌症入侵中起着至关重要的作用。 另一个是Beta3短臂，它可能通过与VII型胶原蛋白和层粘连蛋白6的相互作用在将层粘连蛋白5稳定到地下膜中起重要作用。 我们试图阐明该功能并定位G4-5结构域的SCC促进区域，评估G4-5结构域是癌症治疗的潜在分子靶标。 我们还试图表征层粘连蛋白β3短臂与其假定的配体，VII型胶原蛋白和层粘连蛋白6之间的相互作用，并检查其在皮肤表皮凝聚力和癌发育中的作用。