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

• 批准号: 7155826
• 负责人: TIFFINEY R HARTMAN
• 金额: $ 4.88万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 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/7155826
• 关键词: autosomal dominant trait; centrosome; disease /disorder etiology; disease /disorder model; epithelium; gene expression; genetically modified animals; growth factor; immunofluorescence technique; kinetosome; laboratory mouse; pathologic process; polycystic kidney; postdoctoral investigator; protein localization; protein structure function; sirolimus; tuberous sclerosis; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：结节性硬化症（TSC）是一种常染色体显性遗传疾病，由 TSC1（编码错构蛋白）或 TSC2（编码马铃薯蛋白）基因突变引起，可发生严重的肾囊性疾病。已确定马铃薯蛋白 (TSC2) 和多囊肾病 1 (PKD1) 基因产物多囊蛋白 1 (PC1) 之间的联系。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发病机制中起着核心作用。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 与纤毛和肾囊性疾病联系起来。我们的中心假设是 TSC 依赖性途径的激活是肾囊肿发病机制的关键决定因素。我们将确定（1）TSC 蛋白是否定位于基体或影响 PC1 定位于纤毛，（2）TSC 通路是否调节中心体数量或功能性纤毛的形成，（3）TSC 通路的上调是否会诱导小鼠模型中囊肿的形成。这些是设计针对 TSC 和 ADPKD 囊性疾病的靶向治疗策略的关键步骤。