Functional interaction of claudins in renal ion transport.

紧密连接充当相邻上皮细胞之间的细胞旁扩散屏障，但也包含阳离子、阴离子和/或水的细胞旁通道，其由密蛋白家族的某些成员组成。在肾脏中，claudin具有独特的表达模式，因此定义了特定肾单位节段的细胞旁特性。在第一个资助期间，两个主要的claudin-10（CLDN10）亚型被证明是特别感兴趣的。CLDN10a作为阴离子通道，在近端小管中表达。CLDN10b形成阳离子通道，并在亨利氏袢（TAL）的粗升支中高度表达。患有HELIX综合征（水肿、电解质失衡、泪腺功能障碍、鱼鳞病、口腔干燥症）的患者携带CLDN10基因突变，该突变影响两种亚型或仅影响CLDN10b。为了阐明潜在的病理生理学，我们将研究CLDN10 a和-10 B在肾脏、结肠和汗腺功能中的作用。主要目的是（A）阐明CLDN10 a缺陷小鼠肾脏中的代偿机制，（B）分离TAL和瘦肢中CLDN10 B缺陷对尿渗透压和尿量的影响，（C）表征CLDN10 B在肾外组织中的作用，（D）研究CLDN10b失调在其他疾病的发病机制中的参与，特别是在胆碱能性荨麻疹中，（E）研究斑马鱼CLDN10b/15复合物以鉴定CLDN10b/15选择性过滤器的决定性结构元件。

Tight junctions act as paracellular diffusion barriers between neighboring epithelial cells but also contain paracellular channels for cations, anions and/or water which are composed of certain members of the claudin protein family. In the kidney, claudins have a distinct expression pattern and thus define paracellular properties of specific nephron segments.During the first funding period, the two major claudin-10 (CLDN10) isoforms proved to be of special interest. CLDN10a acts as an anion channel and is expressed in the proximal tubule. CLDN10b forms cation channels and is highly expressed in the thick ascending limb of Henle’s loop (TAL). Extrarenally, it is found in various glands and in the gut.Patients suffering from HELIX syndrome (hypohydrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, xerostomia) carry mutations in the CLDN10 gene which either affect both isoforms or only CLDN10b. To elucidate the underlying pathophysiology, we will investigate the roles of CLDN10a and -10b in kidney, colon and sweat gland function.Major aims are (A) to unravel the compensatory mechanisms in the kidney of Cldn10a-deficient mice, (B) to separate effects of Cldn10b deficiency in TAL and thin limbs on urine osmolarity and volume, (C) to characterize the role of CLDN10b in extrarenal tissues, (D) to study the involvement of CLDN10b dysregulation in the pathogenesis of further diseases, especially in cholinergic urticaria, (E) to investigate the zebrafish Cldn10b/15 complex to identify decisive structural elements of CLDN10b/15 selectivity filters.