Tight junctions: from structure to treatment – T-JUST

Any inner and outer body surface is covered by epithelia. Epithelia are shaped by a layer of cells that, at the same time, form a barrier against the loss of salts and water, and transport salts and water in a coordinated manner. Transport across epithelial layers uses two pathways: the transcellular and the paracellular route. So far, mainly the transcellular pathway has been investigated. Recently, it became evident that this paracellular pathway is highly specific, tightly regulated and causally involved in human diseases. Tight junctions (TJ) are the backbone of the paracellular pathway of epithelial ion transport. Most important for the properties of TJ are members of the claudin (CLDN) family. The set of CLDN expressed at a TJ is extremely tissue-specific; it is responsible for the permeability and selectivity properties of every TJ. CLDN10, -16 and -19 are co-expressed at TJ in the thick ascending limb of the loop of Henle and in ameloblasts. Both tissues express the calcium-sensing receptor CaSR that decreases the paracellular permeability to divalent ions. The aforementioned CLDNs are causally linked to Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (CLDN16 and 19) that associates renal and dental defects, and to HELIX syndrome (CLDN10) that associates dental, renal, cutaneous, and salivary defects.
The bases for the functional properties of the TJ and for the control of those properties are poorly understood. The consequences of the alteration in claudin composition of a TJ to the surrounding tissues are clinically obvious but their pathophysiology remains elusive. In addition, an efficient treatment of TJ diseases is currently not available. Based on those pending questions, on preliminary results recently obtained by the 3 partners of the consortium, and on available animal and cell models and techniques, we aim at

i) identifying how claudins determine the permeability and selectivity of the paracellular pathway, and how claudin properties are controlled

ii) understanding how mutations in claudins are responsible for the development of abnormal mineralization in the close environment of the epithelium (nephrocalcinosis in the kidney (abnormal parenchymal mineralization) and amelogenesis imperfecta (enamel defect) in tooth), and

iii) developing therapeutic strategies of the diseases caused by defects in the paracellular pathway properties; the strategies are based on use of drugs that affect the signalling pathways studied in i).

The proposed study is highly multidisciplinary as it requires a mixed biological and structural approach and will integrate renal physiologists, odontologists, and cell and molecular biologists.
The studies conducted in this proposal will provide key insights regarding the roles of claudins as determinants of permeability, selectivity and structure of tight junctions. They will also help to decipher the mechanisms involved in pathologic consequences of TJ impairment, such as nephrocalcinosis and amelogenesis imperfecta. Finally, they will pave new pathways towards treatment of TJ disorders.