Role of the basement membrane proteins nidogen-1 and -2 in skin physiology and pathology

皮肤基底膜（BM）是一种高度复杂的结构，它将表皮和真皮隔室分开，既提供粘附基质，又提供动态界面，从而控制皮肤的整体结构完整性。它作为一种屏障，限制分子在表皮和真皮层之间的通过，但在生理和病理条件下允许迁移细胞通过。此外，脑转移瘤及其成分是细胞活动的调节剂，如生长、分化、迁移，它们影响组织发育和修复。氮氮原-1和-2是相关的，普遍存在的BM蛋白，被认为在BM组装和稳定中起关键作用。然而，在小鼠中删除任何一个NID基因只会导致轻微的变化，没有改变组织或BM结构，这表明该家族中存在部分冗余。事实上，缺乏两种氮素同种异构体的小鼠在出生后不久就会死亡，表现出一系列可能直接归因于骨髓缺陷的异常。令人惊讶的是，在一些器官中发现超微结构正常的基底膜，表明基底膜中氮原具有组织特异性功能。尽管氮原双零小鼠显示出两种氮原的部分冗余，但在氮原-1或-2缺乏小鼠的伤口愈合研究和肿瘤侵袭实验中，均提供了同种异构体特异性功能的证据。因此，该项目的主要目标将是深入了解同种异构体在皮肤生理和病理中的特定功能，并分析这些差异背后的机制。

The cutaneous basement membrane (BM), which separates the epidermal and dermal compartments, is a highly complex structure providing both an adhesive substrate and a dynamic interface, thus governing the overall structural integrity of the skin. It acts as a barrier that restricts the passage of molecules between epidermis and dermis, but permits the passage of migrating cells under physiological and pathological conditions. Further, BMs and their components are regulators of cellular activities, such as growth, differentiation, migration, and they influence tissue development and repair. The nidogens, nidogen-1 and -2, are related, ubiquitous BM proteins which have been considered to play a key role in BM assembly and stabilization. However, deletion of either of the NID genes in the mouse results in only mild changes with no alteration of tissue or BM architecture indicating partial redundancy within the family. Indeed, mice deficient for both nidogen isoforms die shortly after birth showing a range of abnormalities which could be directly assigned to BM defects. Surprisingly, in some organs ultrastructurally normal BM were found indicating tissue specific functions for nidogens in BMs. Although the nidogen double null mice show partial redundancy for the two nidogens wound healing studies and tumor invasion experiments in either nidogen-1 or -2 deficient mice provide evidence for isoform specific functions. Therefore the main goal of this project will be to gain more insight into the isoform specific functions in skin physiology and pathology and to analyse the mechanisms underlying these differences.