Intracellular calcium in the treatment of polycystic kidney and liver diseases

细胞内钙治疗多囊肾和肝病

• 批准号: 7915676
• 负责人: Sergio A Gradilone
• 金额: $ 7.53万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915676
• 关键词: Affect; Age; Agonist; Animal Model; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Calcium; Cell Line; Cell Proliferation; Cells; Chemicals; Childhood; Cilia; Code; Cyclic AMP; Cyst; Disease; Ductal; Epithelial Cells; Figs - dietary; Fluids and Secretions; Foundations; Genes; Genetic; Goals; Growth; Hepatic; Hepatic Cyst; Hereditary Disease; Infant; Kidney; Lesion; Liver; Liver diseases; Mechanics; Mediating; Morbidity - disease rate; Mutate; Mutation; Organelles; Patients; Perinatal; Phenotype; Polycystic Kidney Diseases; Process; Proprotein Convertase 1; Proprotein Convertase 2; Proteins; Rattus; Reporting; Rodent Model; Role; Sensory; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; apical membrane; biliary tract; cholangiocyte; in utero; kidney epithelial cell; mortality; neonate; novel; novel therapeutics; polycystic liver disease; research study; restoration; therapeutic target

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.

描述（由申请人提供）：常染色体隐性遗传性多囊肾病（ARPKD）是儿科实践中的一种重要遗传性疾病。 ARPKD是新生儿和婴儿的肾脏和肝脏疾病，<30%的受影响新生儿死于子宫内或围产期检测到的肾脏极大增大。 在存活的ARPKD患者中，肝脏病变随着年龄的增长而变得越来越严重，肝脏疾病是发病率和死亡率的主要原因。 在ARPKD以及所有的多囊肝病中，众所周知的遗传缺陷引发肝囊肿的形成，肝囊肿来自胆管细胞，胆管树的上皮细胞。 囊肿进一步扩大，由于至少三个过程的干扰：细胞增殖，细胞-基质相互作用，和液体分泌。 不同的因素，单独或组合，可以影响胆管细胞增殖和促进囊肿生长。 这些潜在因素之一是细胞内钙，已知其水平在囊肿衍生的肾上皮细胞中降低，导致细胞去分化和过度增殖。 本申请的总体目标是检验以下假设：肝囊肿衬里的胆管细胞具有功能障碍的纤毛感觉机制，其导致细胞内钙水平降低，从而导致cAMP介导的过度增殖表型;并且正常细胞内钙水平的药理学恢复可以逆转过度增殖表型。 为了验证这一假设，具体目标1是使用ARPKD动物模型（PCK大鼠）表征细胞内钙的失调及其对肝囊肿形成的下游影响。 具体目标2是评估TRPV 4（钙进入通道）作为治疗靶点的潜在作用。 本申请的实验结果将提供关于控制囊肿胆管细胞增殖的机制的新信息，并将为多囊肝病的合理替代或补充治疗性治疗提供基础。 项目叙述：该申请将检查囊肿在肝脏中形成的细胞机制，并测试一种新的药理学方法，以抑制ARPKD和ADPKD的啮齿动物模型中的胆管细胞过度增殖和囊肿生长，这两种最重要的，不可治愈的遗传性肝病。 这些疾病与已知基因的突变有关，这些基因的蛋白质产物在纤毛中表达，纤毛是从顶端膜延伸到导管腔中的触角样细胞器。 据推测，胆管细胞纤毛感觉机制的异常是肝囊肿形成的中心。