CELL ADHESION DISORDERS IN THE EPIDERMIS

我们将确定表皮细胞粘附蛋白的缺陷 基底 细胞抑制对基底膜（BM）的附着， 附着力- 依赖性细胞功能。 为了实现这一目标，我们确定了 粘合剂 BM配体层粘连蛋白5（epiligrin）和测序的层粘连蛋白5的cDNA产物。 LAMA3 编码层粘连蛋白5的α 3链的基因。 层粘连蛋白5 相互作用 基底细胞中的两种整合素粘附受体， 半桥粒（HD）介导在稳态组织中的锚定， 与 整合素α 3 β 1控制伤口中的细胞迁移。 横 谈谈 在这两种粘附系统之间，平衡两种细胞 锚固 在伤口的稳态和能动性方面。 严重起泡， 上皮 由不完全形成的HD引起，并由缺陷引起 在 层粘连蛋白5在重症交界性 表皮松 大疱病（JEB）。 层粘连蛋白5表达缺陷，如JEB， 应该 破坏粘附依赖性上皮功能， 起泡 上皮细胞 我们希望通过以下方式构建人JEB的小鼠模型： LAMA 3基因的靶向破坏， 重组 到 为了避免胚胎或新生儿死亡，我们将构建一个 鼠标 来自野生型小鼠胚细胞和ES细胞， 突变 LAMA 3基因或通过在可诱导的 启动子 由此产生的凝乳动物将表达野生的 类型和 有缺陷的BM进入成年期， 粘附依赖 功能在于（i）调节增殖和分化， （二） 减少锚定和运动之间的串扰， 增加的细胞侵袭，（iii）用于检查T细胞的系统， 与T细胞淋巴瘤和移植物相关的向表皮性 主机 疾病

We will determine how defects in adhesion proteins of epidermal basal cells inhibit both attachment to the basement membrane (BM) and adhesion- dependent cell function(s). With this goal, we identified the adhesive BM ligand laminin 5 (epiligrin) and sequenced cDNA products of the LAMA3 gene that encode the alpha3 chain of laminin 5. Laminin 5 interacts with two integrin adhesion receptors in basal cells, alpha6beta4 in hemidesmosomes (HDs) to mediate anchorage in homeostatic tissue and with integrin alpha3beta1 to control cell migration in wounds. Cross talk between these two adhesion systems balance needs for both cell anchorage in homeostasis and motility in wounds. Severe blistering of epithelium results from incomplete formation of HDs and is caused by defects in laminin 5 in patients with the gravis form of junctional epidermolysis bullosis (JEB). Defects in expression of laminin 5, as in JEB, should disrupt the adhesion-dependent epithelial functions beyond blistering of the epithelia. We wish to construct a mouse model for human JEB by targeted disruption of the LAMA3 gene using homologous recombination. To avoid embryonic or neonatal lethality we will construct a chymeric mouse from wild type mouse blastocyts and ES cells homozygous for mutations in the LAMA3 gene or by regulation of the mutations under an inducible promoter. The resulting chymeric animals will express both wild type and defective BM into adulthood permitting studies on adhesion-dependent functions on (i) in regulating proliferation and differentiation, (ii) decreased cross talk between anchorage and motility with resulting increased cell invasion, (iii) a system for examining T cell epidermotropism associated with T cell lymphoma and graft verses host disease.