The purpose of this competitive renewal is to continue our ongoing investigation on the role of periostin on renal cyst enlargement and fibrosis in PKD and determine if integrin-linked kinase (ILK), a kinase regulated by periostin-binding to aV-integrins, is a pharmacological target for PKD. Periostin, previously named osteoblast- specific factor 2 (OSF-2), is a newly recognized member of matricellular proteins that also includes thrombospondins, osteopontin, ig-H3, SPARC and connective tissue growth factors. Periostin is expressed in tissues involved in mechanical stress conditions, such as the periodontal ligaments, periosteum and cardiac valves and is secreted into the extracellular matrix (ECM) following acute injury to the heart, skin and other tissues. It directly interacts wit components of the ECM, including collagen and fibronectin, and promotes collagen fibrillogenesis to maintain tissue integrity. Aberrant expression of periostin is associated with fibrosis and tumor growth through activation of pathways involved in cell proliferation, survival and tissue angiogenesis. Periostin is not normally expressed in adult kidney. Our laboratory discovered that periostin was one of the most highly over-expressed genes in human ADPKD cells compared to normal human kidney cells. Periostin accumulates in the ECM adjacent to cysts of ADPKD kidneys in situ and recombinant periostin promotes proliferation of ADPKD cyst epithelial cells. Periostin is also overexpressed in the kidneys of ARPKD patients and several animal models of PKD, suggesting that aberrant expression of periostin is a general feature of PKD regardless of the underlying genetic mutation. Global gene knockout of periostin in pcy/pcy mice, a model of slowly progressive PKD, caused a dramatic decrease in kidney weight/body weight, cyst number and cystic area, proliferating cells and mTOR signaling. There was also reduced interstitial fibrosis, improved kidney function, and a significant increase in the survivalof the mice, suggesting that periostin and its signaling pathway may be potential therapeutic targets for ADPKD. We hypothesize that periostin and possibly other matricellular proteins bind to aV-integrins and stimulate ILK, promoting proliferation and survival of cystic cells and aberrant expression of ECM molecules leading to fibrosis.
In Aim 1, we will determine if periostin overexpression in collecting ducts stimulates ILK signaling, cyst growth and interstitial fibrosis in Pkd1RC/RC hypomorphic mice and pcy/pcy mice.
In aim 2, we will determine if genetic loss of ILK slows PKD progression in Pkd1 mutant and pcy/pcy mice.
In Aim 3, we will delineate signaling pathways downstream of ILK for periostin-induced proliferation, survival and matrix production by human ADPKD cells.
In Aim 4, we will determine if pharmacological inhibition of aV3 integrin and ILK slows or halts PKD progression in Pkd1 mutant mice and pcy/pcy mice.
The goal of this project is to determine the role of integrin-linked kinase (ILK), a key intermediate in the communication between the extracellular matrix and integrin signaling, on periostin-mediated activation of cell proliferation, cyst growth, and interstitial fibrosis in ADPKD.
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