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Roles of TSC1 TDC2 and Rheb in renal cyst pathogenesis

TSC1 TDC2 和 Rheb 在肾囊肿发病机制中的作用

基本信息

批准号：
7413335
负责人：
TIFFINEY R HARTMAN
金额：
$ 5.04万
依托单位：
FOX CHASE CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-19 至 2008-12-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413335
关键词：
Address Apical Autosomal Dominant Polycystic Kidney Cell surface Cells Centrosome Cilia Complex Cyst Cystic Kidney Diseases Cystic kidney Development Dialysis procedure Disease Embryo End stage renal failure Epithelial Cells Fibroblasts Genes Genetic Germ-Line Mutation Immunofluorescence Microscopy Inherited Kidney Kidney Neoplasms Kidney Transplantation Laboratory Finding Lead Link Localized Localized Disease Microtubule-Organizing Center Mus Mutation Numbers Pathogenesis Pathway interactions Physical Dialysis Play Polycystic Kidney Diseases Protein Overexpression Proteins Role Sirolimus Structure TSC1 gene TSC2 gene Testing Transgenic Organisms Tuberous sclerosis protein complex Up-Regulation design early onset human TSC1 protein human TSC2 protein kinetosome mouse model polycystic kidney disease 1 protein therapeutic target

项目摘要

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutation in either the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) gene, in which severe renal cystic disease can occur. Links have been identified between tuberin (TSC2), and polycystin 1 (PC1), the product of the polycystic kidney disease 1 (PKD1) gene. Many proteins associated with renal cystic disease are localized to the primary cilium of renal epithelial cells. It is believed that aberrant ciliary function plays a central role in cyst pathogenesis. We have found that endogenous hamartin is centrosome-localized. Since the centrosome gives rise to the basal body of the primary cilium, this may link TSC with the cilium and with renal cystic diseases. Our central hypothesis is that activation of TSC-dependent pathways is a key determinant of renal cyst pathogenesis. We will determine (1) if TSC proteins localize to the basal body or effect localization of PC1 to the cilia, (2) if TSC pathways regulate centrosome number or formation of functional cilia, (3) if upregulation of TSC pathways induce cyst formation in a mouse model. These are crucial steps toward the design of targeted therapeutic strategies for cystic disease in TSC and ADPKD.

结节性硬化症 (TSC) 是一种常染色体显性遗传疾病，由任一基因突变引起 TSC1（编码错构蛋白）或TSC2（编码马铃薯蛋白）基因，其中可发生严重的肾囊性疾病。已确定马铃薯球蛋白 (TSC2) 和多囊蛋白 1 (PC1)（多囊蛋白的产物）之间存在联系。肾脏疾病 1 (PKD1) 基因。许多与肾囊性疾病相关的蛋白质定位于肾上皮细胞的初级纤毛。人们认为异常的睫状体功能在囊肿中起着核心作用发病。我们发现内源性错构蛋白是中心体定位的。由于中心体产生初级纤毛的基体，这可能将 TSC 与纤毛和肾囊性联系起来疾病。我们的中心假设是 TSC 依赖性途径的激活是肾功能的关键决定因素囊肿发病机制。我们将确定 (1) TSC 蛋白是否定位于基体或影响定位 PC1 至纤毛，(2) TSC 通路是否调节中心体数量或功能性纤毛的形成，(3) 如果 TSC 通路的上调可诱导小鼠模型中囊肿的形成。这些是迈向设计针对 TSC 和 ADPKD 囊性疾病的靶向治疗策略。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway.

DOI：
10.1093/hmg/ddn325
发表时间：
2009-01-01
期刊：
HUMAN MOLECULAR GENETICS
影响因子：
3.5
作者：
Hartman, Tiffiney R.;Liu, Dongyan;Zilfou, Jack T.;Robb, Victoria;Morrison, Tasha;Watnick, Terry;Henske, Elizabeth P.
通讯作者：
Henske, Elizabeth P.

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