Intracellular calcium in the treatment of polycystic kidney and liver diseases

描述（由申请人提供）：常染色体隐性多囊肾病（ARPKD）是儿科实践中重要的遗传性疾病。ARPKD是一种发生于新生儿和婴儿的肾脏和肝脏疾病，小于30%的新生儿因在子宫内或围产期发现肾脏肿大而死亡。在存活的ARPKD患者中，肝脏病变随着年龄的增长而逐渐加重，肝脏疾病是发病率和死亡率的主要原因。在ARPKD以及所有多囊性肝病中，描述良好的遗传缺陷引发肝囊肿的形成，肝囊肿起源于胆管细胞，胆树上皮细胞。由于至少三个过程的干扰，囊肿进一步扩大：细胞增殖、细胞-基质相互作用和液体分泌。不同因素可单独或联合影响胆管细胞增殖，促进囊肿生长。其中一个潜在因素是细胞内钙，已知其水平在囊肿源性肾上皮细胞中降低，导致细胞去分化和过度增殖。

DESCRIPTION (Provided by Applicant): Autosomal recessive polycystic kidney disease (ARPKD) is an important genetic disorder in pediatric practice. ARPKD is a renal and hepatic disease in neonates and infants, and <30% of affected neonates die because of greatly enlarged kidneys detected in utero or in the perinatal period. In surviving ARPKD patients, hepatic lesions become progressively more severe with age, and liver disease is a major cause of morbidity and mortality. In ARPKD, as well as in all the polycystic liver diseases, well described genetic defects initiate formation of hepatic cysts, which arise from cholangiocytes, the epithelial cells lining the biliary tree. Cysts further expand due to disturbances in at least three processes: cell proliferation, cell-matrix interaction, and fluid secretion. Different factors, individually or in combination, could impact cholangiocyte proliferation and promote cyst growth. One of these potential factors is intracellular calcium, level of which is known to be decreased in cyst-derived kidney epithelial cells, leading to cellular dedifferentiation and hyperproliferation. The overall goal of this application is to test the hypothesis that cholangiocytes lining liver cysts have dysfunctional ciliary sensory machinery, which results in decreased levels of intracellular calcium, leading to a cAMP-mediated hyperproliferative phenotype; and that pharmacological restoration of normal intracellular calcium levels could reverse the hyperproliferative phenotype. To test this hypothesis, Specific Aim 1 is to characterize the dysregulation of intracellular calcium and its downstream effects on liver cystogenesis, using an animal model of ARPKD, the PCK rat. Specific Aim 2 is to evaluate the potential role of TRPV4, a calcium entry channel, as therapeutic target. The experimental results from the present application will provide novel information regarding the mechanisms controlling the proliferation of cyst cholangiocytes, and will produce the foundation for a plausible alternative or complementary therapeutic treatment of polycystic liver diseases. PROJECT NARRATIVE: This application will both examine the cellular mechanisms by which cysts form in the liver as well as test a new pharmacological approach to inhibit cholangiocyte hyperproliferation and cyst growth in rodent models of ARPKD and ADPKD, the two most important, incurable, genetic liver diseases. These diseases are associated with mutations in known genes, which protein products are expressed in cilia, antenna-like organelles that extend from the apical membrane into the ductal lumen. It is hypothesized that abnormalities in the sensory machinery of cholangiocyte cilia are central to hepatic cyst formation.