Elucidating nephrocystin function by targeted disruption of the NPHP1-gene

通过靶向破坏 NPHP1 基因阐明肾囊肿素功能

• 批准号: 5209788
• 负责人: Professor Dr. Andreas Kispert
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2000
• 资助国家: 德国
• 起止时间: 1999-12-31 至 2002-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5209788?language=en
• 关键词: Elucidating; nephrocystin; function; targeted; disruption

Nephronophthisis (NPH), an autosomal-recessive human kidney disease, is the most frequent genetic cause of chronic renal failure in childhood. Histologically, the disease is characterized bydisintegration of renal tubular basement membranes, atrophy of adjacent renal tubular cel1s, tubulo=interstitial fibrosis and cyst formation. We have recently identified the responsible gene (NPHP1)by a positional cloning approach. The NPHP 1 gene product "nephrocystin" contains a src-homology 3 (SH3). A full=length murine NPHP 1 cDNA was isolated and tissue expression was characterized.Ubiquitous but low expression was found at embryonic stages and in an adult tissues except testis where strong expression was confined to germ cells of the first meiotic division and thereafter.Multiple lines of evidence strongly argue that histological changes in NPH are due to a role of nephrocystin in cell-matrix signaling at focal adhesions.Within this project, an animal model for human NPH will be generated by targeted disruption of the mouse NPHP 1 gene. Mice homozygous mutant for a likely nuJ1 allele of NPHP 1 will be phenotypically characterized. Since nephrocistin represents a novel gene product, we expect from these studies the elucidation of novel mechanisms of cell-matrix and cell-cell signaling in developing and adult kidney, and possibly in other organs. Such insights may also shed light on disease mechanisms of other diseases of the "NPH-complex".

肾病综合征（NPH）是一种常染色体隐性遗传的人类肾脏疾病，是儿童慢性肾功能衰竭最常见的遗传原因。组织学上以肾小管基底膜崩解、邻近肾小管细胞萎缩、肾小管间质纤维化和囊肿形成为特征。我们最近通过定位克隆方法确定了负责基因（NPHP 1）。NPHP 1基因产物“肾囊蛋白”含有src同源性3（SH 3）。从小鼠组织中分离到一个全长的NPHP 1 cDNA，并对其进行了组织表达的鉴定。在胚胎期和成年组织中发现了广泛但低表达的NPHP 1 cDNA，但在成年组织中发现了NPHP 1 cDNA，而在成年组织中，除了睾丸外，其强表达仅限于第一次减数分裂的生殖细胞和其后的生殖细胞。多条证据有力地表明，NPH的组织学变化是由于肾囊蛋白在粘着斑的细胞-基质信号传导中的作用。在本项目中，人NPH的动物模型将通过小鼠NPHP 1基因的靶向破坏来产生。将对NPHP 1的可能nuJ 1等位基因的小鼠纯合突变体进行表型表征。由于nephrocistin代表了一种新的基因产物，我们期望从这些研究中阐明细胞基质和细胞间信号传导在发育和成人肾脏中的新机制，并可能在其他器官中。这些见解也可能揭示其他疾病的“NPH复合体”的疾病机制。