Heparin-Binding EGF in Autosomal Recessive PKD

常染色体隐性遗传性多囊肾病(ARPKD)是世界各国发病率和死亡率的重要原因。 儿童和青少年。最近的重大进展已经确定了致病基因PKHD1和 异常蛋白产物，纤维囊藻毒素。大多数形式的PKD的一个重要特征是过度表达和异常 表皮生长因子相关生长因子及其共有受体EGF受体的定位 (EGFR)。金属蛋白酶EGFR或肿瘤坏死因子-α转换酶(TACE)的抑制剂 介导EGF相关生长因子的裂解，产生可溶性形式，改善囊性 几种PKD动物模型中的肾脏疾病。然而，抑制EGFR并不能改善囊性肾 PCK大鼠的疾病，该疾病在大鼠的PKDH1同源物中含有突变。我们现在证明了肝素结合 表皮生长因子(HB-EGF)及其受体ErbB4过度表达 错误定位于PCK大鼠和Bpk模型小鼠肾脏的集合管(CT)囊肿 ARPKD.我们还发现HB-EGF在培养的CT细胞中表达上调。这些共同的特征表明 Hb-EGF/ErbB4可能是ARPKD发病机制中最相关的生长因子途径。HB-EGF是 被MAP激酶ERK上调，ERK是环磷酸腺苷的靶标，第二信使是 在PKD中上调。假设在囊性上皮细胞中，HB-EGF和ErbB4过表达和 错误定位是由cAMP依赖的ERK1/2激活引起的。这些信号分子还 刺激TACE活化，HB-EGF脱落，从而促进肾小管上皮细胞 增殖，其他EGF相关生长因子的诱导和ERK1/2的进一步激活。具体目标 目的：(1)确定Hb-EGF/ErbB4轴在囊性发育和疾病中的需要 ARPKD BPKK模型的研究进展：(2)明确TACE在囊性肾发病机制中的作用 (3)cAMP和ERK 1/2在介导HB-EGF中的作用 囊性上皮中高表达。这项研究的总体目标是描绘调解人和 将cAMP和ERK 1/2激活等上游事件与HB-EGF/ErbB4联系起来的信号通路 过度表达和细胞增殖等囊性过程。这些研究将提供重要的 对ARPKD疾病发病机制的洞察，并可能确定潜在的新治疗靶点。

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of morbidity and mortality in children and adolescents. Major recent advances have identified the causative gene, PKHD1 and the abnormal protein product, fibrocystin. A key feature of most forms of PKD is overexpression and abnormal localization of epidermal growth factor (EGF)-related growth factors and their shared receptor, EGF receptor (EGFR). Inhibitors of EGFR or tumor necrosis factor-alpha converting enzyme (TACE), a metalloproteinase that mediates cleavage of EGF-related growth factors to produce the soluble forms, ameliorates cystic kidney disease in several PKD animal models. However, EGFR inhibition does not ameliorate cystic kidney disease in the PCK rat, which harbors a mutation in rat homologue of PKDH1. We now show that heparinbinding EGF (HB-EGF), an EGF-related growth factor, and its receptor, ErbB4, are overexpressed and mislocalized in the collecting tubule (CT) cysts of kidneys of both the PCK rat and the bpk mouse models of ARPKD. We also show that HB-EGF is upregulated in cultured CT cells. These shared features suggest that HB-EGF/ErbB4 may be the most relevant growth factor pathway in ARPKD pathogenesis. HB-EGF is upregulated by the MAP kinase, ERK , which is a target of cyclic AMP, a second messenger that is upregulated in PKD. The hypothesis is that in cystic epithelium, HB-EGF and ErbB4 overexpression and mislocalization are induced by cAMP-dependent ERK 1/2 activation. These signaling molecules also stimulate activation of TACE, and resultant HB-EGF shedding thereby promoting tubular epithelial cell proliferation, induction of other EGF-related growth factors and further ERK 1/2 activation. The specific aims are (1) To determine the requirement for the HB-EGF/ErbB4 axis in cyst development and disease progression in the bpk model of ARPKD; (2) To define the role of TACE in the pathogenesis of cystic kidney in disease in ARPKD; and (3) To delineate the role of cAMP and ERK 1/2 in mediating HB-EGF overexpression in cystic epithelia. The overall goals of this research are to delineate that mediators and signaling pathways that link upstream events, such as cAMP and ERK 1/2 activation, to HB-EGF/ErbB4 overexpression and cystogenic processes such as cell proliferation. These studies will provide important insights into ARPKD disease pathogenesis and may identify potential new therapeutic targets.