Our overall goal is to define the molecular mechanisms whereby cell-extracellular matrix (ECM) interactions regulate renal tubulogenesis. Renal tubules are highly ordered terminally differentiated structures consisting of polarized epithelial cells derived from either the ureteric bud (UB) or the metanephric mesenchyme (MM). Because biological changes occurring during renal tubulogenesis are best characterized in the context of renal development, we use the UB as a model to study basic mechanisms of tubule formation. However these processes are also critically important in understanding the pathophysiology of congenital renal diseases such as polycystic kidney disease and renal dysplasia which affect the adult Veteran population. Furthermore, many features of renal tubule development are recapitulated in renal recovery following acute kidney tubule injury, which is a major cause of morbidity and mortality in Veterans. The UB originates from the Wolffian duct and gives rise to the collecting system of the mature kidney from the collecting ducts (CD) to the trigone of the bladder. The renal papilla and CDs develop by undergoing iterative branching morphogenesis, a complex process that is, at least in part, dependent on cell-ECM interactions. We previously demonstrated that integrins are critical for tubulogenesis. Integrins are transmembrane receptors for ECM composed of non-covalently bound and subunits. 1 is the most abundantly expressed integrin subunit in the kidney and can bind 12 different a subunits. The 1 cytoplasmic tail plays a critical role in integrn function by binding multiple cytoplasmic proteins which regulate integrin- mediated signaling and cytoskeleton modulation. The integrin linked kinase (ILK)/Pinch/Parvin (IPP) complex is one of the key scaffolding hubs that bind the integrin 1 cytoplasmic tail. We previously showed that ILK and Pinch are critical for tubule formation; however, the role of Parvin is still unknown. In this Merit renewal we will define how the IPP complex interacts with the 1 integrin tail and how specific interactions among the various IPP components regulate renal tubulogenesis by testing the hypotheses that a) distinct IPP components have specific roles in mediating renal tubulogenesis and b) IPP/1 integrin interactions are dynamically regulated by certain 1 tail residues. To test these hypotheses we will perform the following 3 aims. 1) Determine the mechanisms whereby ILK regulates development and maintenance of the kidney collecting system. 2) Determine the role of Parvin in the development and maintenance of the kidney collecting system. 3) Determine the mechanism whereby the 1 integrin cytoplasmic tail recruits the IPP complex. This study will generate novel insights into the molecular basis whereby 1 integrins and the ILK/Pinch/Parvin complex regulate renal tubulogenesis. Understanding this basic cell biological process will help with our comprehension of the pathophysiology of congenital renal diseases resulting in abnormal tubule formation as well as how tubules recover from acute injury. Ultimately a better understanding of these processes might lead to novel therapeutics for the treatment of renal disease caused by dysregulated tubule formation.
We anticipate that this study will generate novel insights into the role of integrins and their binding partners, Integrin linked kinase/Pinch/Parvin in renal tubulogenesis. This knowledge is fundamental to our understanding of how the renal collecting system functions and could potentially define new etiologies for dysmorphic dysgenic kidneys, cystic renal diseases and decreased nephron formation. All of these conditions either cause chronic renal disease or increase the rate of its progression.
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