Mechanisms of Fibrillin-Polycystin-1 Interaction

Fibrillin-Polycystin-1 相互作用的机制

• 批准号: 6997618
• 负责人: CONNIE WANG
• 金额: $ 3.08万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997618
• 关键词: DNA binding protein; Marfan syndrome; autosomal dominant trait; cardiovascular disorder; fibrillin; gene interaction; laboratory mouse; pathologic process; polycystic kidney; postdoctoral investigator; transforming growth factors

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.

描述（由申请方提供）：血管并发症是ADPKD发病率和死亡率的重要原因。推测多囊蛋白在维持血管完整性中起重要作用，但多囊蛋白在血管系统中的精确细胞功能尚未确定。我们相信PKD和FBN之间的关系可能会带来令人兴奋的新线索，FBN突变导致马凡氏综合征，也具有突出的血管表型。近年来的研究表明TGF-β信号通路的过度活化可能在马凡氏病的发病机制中起一定作用。少数ADPKD家系具有类似马凡氏综合征的特征，提示这两种疾病可能相关。初步研究表明，transheterozygotes增加严重的心脏缺陷和异常的主动脉壁的组织的发生率。该建议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-β信号通路的协同调节。我们将使用来自transheterozygous小鼠的组织和细胞来检查FGF-b途径中的各个步骤。我们将检测到PKD 1胞外区的配体可能是PKD 1胞外区的配体。第二，我们研究了PKD 1过表达通过STAT-1依赖性诱导SMAD 7下调TGF-β信号转导。