Mechanisms of Fibrillin-Polycystin-1 Interaction

描述（由申请人提供）：血管并发症是ADPKD发病和死亡的重要原因。推测多囊毒素在维持血管完整性中起重要作用，但多囊毒素在血管中的确切细胞功能尚未明确。我们相信，令人兴奋的新线索可能来自PKD和FBN之间的关系，FBN的突变导致马凡氏综合征，也具有突出的血管表型。最近的研究表明，TGF-b信号通路的过度活性可能在马凡氏病的发病机制中发挥作用。少数具有类似马凡氏综合征特征的ADPKD家族提示这两种疾病可能存在相关性。初步研究表明，异杂合子增加了严重心脏缺陷和主动脉壁组织异常的发生率。本研究的重点是了解这种遗传相互作用的机制。在第一个目标中，我们将测试遗传相互作用是由于TGF-b信号通路的协同调节。我们将使用转杂合子小鼠的组织和细胞来检测FGF-b通路的各个步骤。我们将测试原纤维蛋白可能是PKD1细胞外结构域的配体。第二，我们研究了PKD1过表达通过stat1依赖性诱导SMAD7下调TGF-b信号。

DESCRIPTION (provided by applicant): Vascular complications are significant causes of morbidity and mortality in ADPKD. Speculation that polycystins play important role in maintaining vessel integrity, but precise cellular function of polycystins in vasculature has not been defined. We believe that exciting new clues may come from relationship between PKD and FBN whose mutation causes Marfan's syndrome that also has a prominent vascular phenotype. Recent work suggests over activity of the TGF-b signaling pathway may play role in Marfan's pathogenesis. A small number of ADPKD families with features similar of Marfan's syndrome suggest these 2 diseases might be related. Preliminary studies demonstrate transheterozygotes increased incidence of severe cardiac defects and abnormalities in organization of aortic wall. This proposal focuses on understanding mechanism for this genetic interaction. In 1st aim we will test that genetic interaction is due to cooperative modulation of TGF-b signaling pathway. We'll use tissues and cells from transheterozygous mice to examine various steps in FGF-b pathway. We'll test that fibrillin may be ligand for extracellular domain of PKD1. In 2nd, we examine overexpression of PKD1 down regulates TGF-b signaling via the STAT-1 dependent induction of SMAD7.