? ADPKD is the most common life threatening hereditary disease in the USA. It affects about 1:400 to 1:1000 people. ADPKD accounts for about 5-10% of end-stage renal failure in the USA requiring dialysis and renal transplantation. The Han:SPRD rat model and mice with a targeted mutation in the Pkd2 gene closely resemble human ADPKD and present an opportunity to evaluate the therapeutic effect of agents that have the potential to interfere with one or more of the pathogenic elements of ADPKD. Angiogenesis is a feature of human polycystic kidneys and may provide the blood supply for progressive cyst formation. The effect of angiogenesis inhibition on cyst formation and subsequent renal failure is not known. One of the central components of angiogenesis is the growth factor VEGF and its receptors VEGFR-1 and VEGFR-2. VEGF receptor inhibitors have been widely used in animal studies of cancer in vivo to dramatically alter a variety of pathological processes. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby VEGF may function in an autocrine fashion to stimulate cystic epithelial cell proliferation as well as in a paracrine fashion to stimulate vascular endothelial cell proliferation and angiogenesis.
In specific aim 1, we shall characterize the angiogenesis, VEGF and VEGF receptor expression in ADPKD.
In specific aim 2 we shall use an in vitro model of cyst formation to identify the role of VEGF on cyst epithelial proliferation.
Specific aim 3 focuses on in vivo studies using VEGF receptor inhibitors. The relevance of these studies to clinical ADPKD is substantial and the results should provide leads to altering the course of ADPKD. This is particularly true because of the current availability of VEGF receptor antagonists and their proven beneficial effect in cancer studies ? ?
|Liu, Bin; Li, Chenghai; Liu, Zijuan et al. (2012) Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney disease. BMC Nephrol 13:109|
|Li, Chenghai; Liu, Bin; Dai, Zonghan et al. (2011) Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC). Cancer Biol Ther 12:872-80|
|Zhuang, Chunmei; Tang, Hongxing; Dissanaike, Sharmila et al. (2011) CDK1-mediated phosphorylation of Abi1 attenuates Bcr-Abl-induced F-actin assembly and tyrosine phosphorylation of WAVE complex during mitosis. J Biol Chem 286:38614-26|
|Yu, Weidong; Sun, Xiaolin; Tang, Hongxing et al. (2010) Inhibition of class II phosphoinositide 3-kinase gamma expression by p185(Bcr-Abl) contributes to impaired chemotaxis and aberrant homing of leukemic cells. Leuk Lymphoma 51:1098-107|
|Sun, Xiaolin; Li, Chenghai; Zhuang, Chunmei et al. (2009) Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells. Carcinogenesis 30:2109-16|
|Tao, Yunxia; Zafar, Iram; Kim, Jun et al. (2008) Caspase-3 gene deletion prolongs survival in polycystic kidney disease. J Am Soc Nephrol 19:749-55|
|Yu, Weidong; Sun, Xiaolin; Clough, Nancy et al. (2008) Abi1 gene silencing by short hairpin RNA impairs Bcr-Abl-induced cell adhesion and migration in vitro and leukemogenesis in vivo. Carcinogenesis 29:1717-24|
|Sun, X; Li, Y; Yu, W et al. (2008) MT1-MMP as a downstream target of BCR-ABL/ABL interactor 1 signaling: polarized distribution and involvement in BCR-ABL-stimulated leukemic cell migration. Leukemia 22:1053-6|
|Tao, Y; Kim, J; Yin, Y et al. (2007) VEGF receptor inhibition slows the progression of polycystic kidney disease. Kidney Int 72:1358-66|