Molecular pathophysiology of the biological barrier regulation of molecular passage through paracellular spaces.

紧密连接是细胞间的连接，靠近最外侧的顶端膜表面。它们有两种功能，屏障功能和栅栏功能。前者调节离子、水和大分子通过细胞旁空间，后者维持细胞极性。一旦紧密连接受到干扰，就会出现水肿、黄疸、腹泻等疾病。在癌细胞中，紧密连接随着去分化的进展而减少。在这个项目中，我们进行了如下演示。肝细胞核因子-4a是紧密连接形成的关键转录因子。Claudin-1和claudin-5分别在MAP激酶和蛋白激酶A的胞质结构域具有一致的序列。间隙连接细胞间通讯增强了紧密连接功能。病理状态下肝脏间隙和紧密连接的功能主要受p38 MAP激酶信号转导通路调控。Occludin可能部分介导生存信号。在人子宫内膜癌中，occludin的表达随着肿瘤分级的增加而逐渐降低。甘油醛衍生的晚期糖基化终产物诱导人星形胶质细胞中VEGF表达并降低GDNF表达，提示糖尿病视网膜病变的主要原因是视网膜中毛细血管的高渗透性。

Tight junctions are intercellular junctions adjacent to the apical most lateral membrane surface. They have two functions, a barrier function and a fence function. The former regulates the passage of ions, water and macromolecules through paracellular spaces and the latter maintains cell polarity. Once tight junctions are disturbed, illnesses such as edema, jaundice, diarrhea etc. can develop. In cancer cells, tight junctions decrease as dedifferentiation progresses. In this project, we demonstrated as follows.1. Hepatocyte nuclear factor-4a is a key transcriptional factor of tight junction formation.2. Claudin-1 and claudin-5 have consensus sequence in their cytoplasmic domains for MAP kinase and Protein kinase A, respectively.3. Gap junctional interecellular communication enhances tight junction function.4. In livers under pathological conditions, functions of gap and tight junctions are mainly regulated by p38 MAP kinase signal transduction pathway.5. Occludin may in part mediate survival signal.6. The expression of occludin progressively decreases in parallel with increasing grade of in human endometrial carcinomas.7. Glyceraldehyde-derived advanced glycation end-products induces VEGF expression and reduces GDNF expression in human astrocytes, suggesting the main cause of diabetic retinopathy, in terms of highly permeable capillaries in the retina.