Integrins are transmembrane heterodimeric glycoproteins composed of 1 and 2 subunits that mediate the interactions between cells and extracellular matrix (ECM). In humans there are 18 1 and 8 2 subunits, which combine in a restricted manner to form dimers, each of which exhibit different ligand binding properties. Integrins can be classified by these ligand binding properties into collagen, laminin and RGD binding receptors. The principal laminin binding integrins are 1321, 1621 and 1624. Integrin-mediated cell interactions with basement membranes are critical for normal development of the kidney collecting system. Key components of basement membranes are laminins which are trimers consisting of 1, 2 and 3 subunits. Although much work has been done to show the requirement of laminins in the development and function of the glomerulus of the kidney;their role in renal collecting system development in vivo is poorly defined. In this context, until recently only the 15 chain containing laminins were known to play a role in ureteric bud (UB) development in vivo. In the last funding cycle we showed that the 13, 31 and 32 chains of laminins are also required for UB development. There is controversy as to the role of the laminin binding integrins in the developing kidney collecting system. Although all 3 principal laminin binding integrins are expressed, their roles are not well defined. Only integrin 1321 has been shown to play a role in UB development in vivo, however we have shown that the integrins 1621 and 1624 play a role in UB development in vitro. During the last funding cycle we demonstrated that deleting the 21 integrin subunit in the UB in vivo resulted in significantly worse developmental abnormalities than when the 13 subunit was deleted, suggesting that other 121 integrins are important for this developmental process. In this proposal we aim to delineate the specific roles of the laminin receptors 1321, 1621 and 1624 in UB development in vivo and determine the mechanisms whereby these integrins regulate this process. We will delete the 13, 16, and 24 integrin subunits either alone or in combination in the developing UB by crossing integrin-floxed mice with hoxb7cre mice to test the hypothesis that the three laminin-binding integrins, namely 1321, 1621 and 1624, are required and act synergistically for the UB to develop and function normally in health and disease. This hypothesis will be tested in the following 3 aims. 1) Determine the role of the specific laminin receptors in UB development and function. 2) Determine the roles of the 13, 16and 24 integrin subunits in maintaining the structural integrity of the renal collecting system.
Aim 3) Determine the mechanism whereby the specific laminin receptors regulate renal epithelial cell branching morphogenesis.
We anticipate that this study will generate novel insights into the role of laminin receptors in the development of the collecting system of the kidney. This knowledge is fundamental to our understanding of how the renal collecting system functions and why there is an increased incidence of renal abnormalities in patients with bullous skin diseases.
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