This proposal aims to define the role of two major ?1 integrin binding proteins, talins and kindlins, in regulating kidney tubule responses to injury. Integrins are comprised of 18 ? and 8 ? subunits combined in a restricted manner to form various heterodimers, each of which exhibits different binding properties to extracellular matrix (ECM) components. ?1, the most abundantly expressed integrin subunit in the kidney, binds 12 ? subunits. Its cytoplasmic tail (CT) interacts with multiple proteins that promote integrin-mediated adhesion, migration and bidirectional signaling. Talins and kindlins are the best defined molecules that promote integrin activation. Two talin and 2 kindlin isoforms expressed in kidney bind to 2 canonical NxxY motifs found in most ? integrin tails: talins to the membrane-proximal motif and kindlins to the membrane distal. We showed that deleting ?1 integrin at the initiation of collecting system development caused dysmorphic and dysplastic kidneys, while removing ?1 post development did not result in morphological abnormalities, but caused severe tubulointerstitial fibrosis following unilateral ureteric obstruction (UUO). Similarly, deletion of ?1 from the proximal kidney tubule post- development did not result in morphological defects, but there was a major urine-concentrating deficiency and increased susceptibility and failure of recovery from acute injury. Surprisingly, when we deleted either all talin or kindlin isoforms in the developing collecting system, the mice were anephric. These phenotypes, which are much more severe than when ?1 integrin was deleted, suggest that talins and kindlins have functions that extend beyond those involving their ability to bind and activate ?1 integrin. We therefore developed tools to define the specific roles of the various talin and kindlin isoforms in mediating and/or resolving kidney injury. In this grant we will utilize these tools to test the hypothesis that talins and kindlins regulate the response of kidney tubules to injury by distinct ?1 integrin-dependent and -independent mechanisms. This hypothesis will be tested in the following 2 aims.
Aim 1. Determine the mechanisms whereby talins regulate the response of kidney tubules to injury. How talins modulate the response of the kidney to tubular injury will be tested in UUO and prolonged ischemia reperfusion models and mechanistic studies will be performed on polarized renal tubule epithelial cells.
Aim 2. Determine the mechanisms whereby kindlins regulate the response of kidney tubules to injury. We will contrast the response to injury of talin and kindlin mice as well as their differences in their cell function, to define the distinct roles and mechanisms of action of these proteins in renal tubular epithelial biology and pathology.
We anticipate that this study will generate novel insights into the role of kindlins and talins in the response of renal tubules to chronic kidney injury. This knowledge is fundamental to our understanding of how renal tubules function in health and disease. Chronic tubule injury is an important cause of end stage renal disease in both the general and Veteran Population.
|Tseng, Hui-Yuan; Samarelli, Anna V; Kammerer, Patricia et al. (2018) LCP1 preferentially binds clasped ?M?2 integrin and attenuates leukocyte adhesion under flow. J Cell Sci 131:|
|Sausville, Lindsay N; Gangadhariah, Mahesha H; Chiusa, Manuel et al. (2018) The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer Res 78:4865-4877|
|Brown, Kyle L; Banerjee, Surajit; Feigley, Andrew et al. (2018) Salt-bridge modulates differential calcium-mediated ligand binding to integrin ?1- and ?2-I domains. Sci Rep 8:2916|
|Cleghorn, Whitney M; Bulus, Nada; Kook, Seunghyi et al. (2018) Non-visual arrestins regulate the focal adhesion formation via small GTPases RhoA and Rac1 independently of GPCRs. Cell Signal 42:259-269|
|Polosukhina, Dina; Love, Harold D; Moses, Harold L et al. (2017) Pharmacologic Inhibition of ?-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor. Oncol Res 25:1653-1664|
|Polosukhina, Dina; Love, Harold D; Correa, Hernan et al. (2017) Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors. Mol Oncol 11:405-421|
|Borza, Corina M; Su, Yan; Tran, Truc-Linh et al. (2017) Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis. Matrix Biol 57-58:258-271|
|Mathew, Sijo; Palamuttam, Riya J; Mernaugh, Glenda et al. (2017) Talin regulates integrin ?1-dependent and -independent cell functions in ureteric bud development. Development 144:4148-4158|
|Williams, Ashley S; Trefts, Elijah; Lantier, Louise et al. (2017) Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance. Diabetes 66:325-334|
|Viquez, Olga M; Yazlovitskaya, Eugenia M; Tu, Tianxiang et al. (2017) Integrin alpha6 maintains the structural integrity of the kidney collecting system. Matrix Biol 57-58:244-257|
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