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

紧密连接是细胞间的连接，与顶端最外侧的膜表面相邻。它们有两个功能，屏障功能和围栏功能。前者调节离子、水和大分子通过细胞旁空间的通道，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。在本项目中，我们做了如下演示：1.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在其胞浆区分别具有MAP激酶和蛋白激酶A的共有序列.细胞间缝隙连接通讯增强紧密连接功能.在病理状态下，肝脏间隙连接和紧密连接的功能主要受p38 MAP激酶信号转导通路的调节. Occludin可能部分介导生存信号. occludin在子宫内膜癌中的表达随着子宫内膜癌分级的增加而逐渐降低.在人星形胶质细胞中，甘油醚衍生的晚期糖基化终产物诱导VEGF表达并降低GDNF表达，这表明糖尿病视网膜病变的主要原因，就视网膜中的高渗透性毛细血管而言。

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.