Kidney development and cystogenesis in Medaka

青鳉的肾脏发育和囊肿发生

基本信息

批准号：
6951140
负责人：
TOMOKO OBARA
金额：
$ 15.15万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6951140
关键词：
autosomal dominant trait disease /disorder model gene expression gene mutation genetically modified animals medaka messenger RNA nephrogenesis polycystic kidney polymerase chain reaction protein protein interaction renal tubule

项目摘要

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease occurring at a frequency of 1:1000 in humans and characterized by cyst formation in kidney tubules, deregulated fluid transport and alteration of extracellular adhesion. ADPKD is caused by mutations in the PKD1 or PKD2 gene that encode polycystin-1 and polycystin-2, respectively. The primary causes and mechanisms of cyst formation in ADPKD remain elusive. Our attempts to knockdown pkdl in zebrafish failed because of gene redundancy. Medaka is a unique inbred aquatic vertebrate fish model system, which shows lower redundancy in gene number compared to zebrafish. The use of medaka provides an opportunity to develop a novel system to study organogenesis and to understand the mechanisms of cystogenesis. Given that PKD1 mutations account for 85% of all ADPKD cases in humans, we have targeted pkdl in medaka to understand its function(s). Preliminary results demonstrate that targeting pkdl in medaka (in contrast to zebrafish) causes prronephric cysts formation. We have also established a system using medaka for studies of kidney, cystogenesis that is sensitive for the defect of polycystin-1 interacting proteins such as polycystin-2, which can be used to assess the in vivo relevance of the large number of polycystin-1 interacting proteins. In specific aim 1, we will test the in vivo function of specific polycystin-1 motifs by disrupting pkdl mRNA splicing and generate an allelic series of deletions in medaka. For this purpose, we propose to use our urogenital specific medaka transgenic GFP line to monitor the progress of cyst formation, and to analyze the kidney phenotypes as well as other potential defects in organogenesis caused by the defers. In specific aim 2, we will validate the biological significance of polycystin-1 interacting proteins.

描述（由申请人提供）：常染色体显性多囊肾病（ADPKD）是一种遗传性疾病，在人类中发生的频率为 1:1000，其特征是肾小管中形成囊肿、液体运输失调和细胞外粘附改变。 ADPKD 是由分别编码多囊蛋白 1 和多囊蛋白 2 的 PKD1 或 PKD2 基因突变引起的。 ADPKD 囊肿形成的主要原因和机制仍不清楚。由于基因冗余，我们在斑马鱼中敲低 pkdl 的尝试失败了。青鳉是一种独特的近交水生脊椎动物模型系统，与斑马鱼相比，其基因数量冗余度较低。青鳉的使用提供了开发新系统来研究器官发生和了解囊肿发生机制的机会。鉴于 PKD1 突变占人类所有 ADPKD 病例的 85%，我们以青鳉中的 pkdl 为目标，以了解其功能。初步结果表明，针对青鳉鱼（与斑马鱼相反）的 pkdl 会导致肾前囊肿形成。我们还建立了一个利用青鳉进行肾脏、囊肿发生研究的系统，该系统对多囊蛋白-1相互作用蛋白（如多囊蛋白-2）的缺陷敏感，可用于评估大量多囊蛋白-1的体内相关性相互作用的蛋白质。在具体目标 1 中，我们将通过破坏 pkdl mRNA 剪接并在青鳉中产生一系列等位基因缺失来测试特定多囊蛋白-1 基序的体内功能。为此，我们建议使用我们的泌尿生殖特异性青鳉转基因 GFP 系来监测囊肿形成的进展，并分析肾脏表型以及由延迟引起的器官发生中的其他潜在缺陷。在具体目标 2 中，我们将验证多囊蛋白-1 相互作用蛋白的生物学意义。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures.

发育可塑性成年小鼠肾细胞系自发产生多个成年肾脏结构。

DOI：
10.1016/j.bbrc.2015.06.130
发表时间：
2015
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Webb,CarolF;Ratliff,MichelleL;Powell,Rebecca;Wirsig-Wiechmann,CelesteR;Lakiza,Olga;Obara,Tomoko
通讯作者：
Obara,Tomoko

Wtip is required for proepicardial organ specification and cardiac left/right asymmetry in zebrafish.

DOI：
10.3892/mmr.2016.5550
发表时间：
2016-09
期刊：
Molecular medicine reports
影响因子：
3.4
作者：
Powell R;Bubenshchikova E;Fukuyo Y;Hsu C;Lakiza O;Nomura H;Renfrew E;Garrity D;Obara T
通讯作者：
Obara T

A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes.

DOI：
10.1038/emboj.2010.18
发表时间：
2010-04-07
期刊：
EMBO JOURNAL
影响因子：
11.4
作者：
Giamarchi, Aurelie;Feng, Shuang;Rodat-Despoix, Lise;Xu, Yaoxian;Bubenshchikova, Ekaterina;Newby, Linda J.;Hao, Jizhe;Gaudioso, Christelle;Crest, Marcel;Lupas, Andrei N.;Honore, Eric;Williamson, Michael P.;Obara, Tomoko;Ong, Albert C. M.;Delmas, Patrick
通讯作者：
Delmas, Patrick

Medaka fish, Oryzias latipes, as a model for human obesity-related glomerulopathy.

DOI：
10.1016/j.bbrc.2013.01.053
发表时间：
2013-02-22
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Ichimura, Koichiro;Kawashima, Yusuke;Nakamura, Tomomi;Powell, Rebecca;Hidoh, Yuya;Terai, Shuji;Sakaida, Isao;Kodera, Yoshio;Tsuji, Takashi;Ma, Jian-Xing;Sakai, Tatsuo;Matsumoto, Hiroyuki;Obara, Tomoko
通讯作者：
Obara, Tomoko

Workshop report: The medaka model for comparative assessment of human disease mechanisms.