Cell Cycle Dependent Mechanisms of Renal Hypertrophy

肾肥大的细胞周期依赖性机制

• 批准号: 7017009
• 负责人: DANIEL J RILEY
• 金额: $ 19.62万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017009
• 关键词: AP1 protein; cell cycle; cell growth regulation; cyclin dependent kinase; diabetic nephropathy; gel mobility shift assay; gene expression; genetic regulation; genetically modified animals; glomerulosclerosis; glucose; immunoprecipitation; insulin dependent diabetes mellitus; kidney cell; kidney hypertrophy; laboratory mouse; mesangium; phosphorylation; protooncogene; retinoblastoma protein; site directed mutagenesis; western blottings

DESCRIPTION (Provided by applicant): Early in diabetic nephropathy glomerular mesangium and renal tubules hypertrophy. Mesangial hypertrophy is an important, perhaps reversible, step preceding glomeruloscierosis and overt nephropathy. Using unique transgenic mice overexpressing retinoblastoma protein (Rb) and mesangial cells expressing Rb from a tetracycline-confrollable promoter system, we have discovered that renal and glomerular mesangial cell hypertrophy occur with both diabetes mellitus and with over expression of hypophosphorylated Rb. Preliminary data has shown that when Rh is over expressed, neither kidneys nor mesangial cells hypertrophy further in diabetic conditions. Our hypothesis to explain these observations is that excess glucose results in specific, cyclin-dependent phosphorylation of Rb protein during early Gi phase, and that Rb is involved distally in a pathway of glomerular mesangial cell hypertrophy. To test this hypothesis, three Specific Aims are proposed: (1) Determine whether renal and glomerular hypertrophy caused by diabetes mellitus in vivo and mesangial cell hypertrophy caused by high glucose concentrations ex vivo are dependent on activation of specific C1 phase cyclin-cdk complexes and specific phosphorylations of Rb protein. (2) Determine how high glucose regulates cdk4-cyclin Dl activity and Rb phosphorylation in mesangial cells by examining patterns of gene regulation including transcription of the cyclin D1 gene itself and of events controlled by relevant transcription factors including AP-1. (3) Test the requirement for Cl cyclin dependent kinase activation and specific cdk4-dependent phosphorylations of Rb protein for diabetic renal hypertrophy in vivo and mesangial cell hypertrophy in culture. Transgenic mice with strategic phosphorylation sites in Rb inactivated by site-directed mutagenesis will be generated and the effects of type 1 diabetes mellitus will be examined in them. Primary mesangial cells will also be cultured from the mice and more detailed studies on hypertrophy and GI cell cycle regulation by cdks and Rb conducted in vitro.

描述（由申请人提供）：糖尿病肾病早期肾小球 系膜和肾小管肥大。系膜肥大是一个重要的， 可能是可逆的，在肾小球硬化和明显肾病之前的步骤。 使用过表达视网膜母细胞瘤蛋白（Rb）的独特转基因小鼠， 从四环素可调控启动子系统表达Rb的系膜细胞， 我们发现肾脏和肾小球系膜细胞肥大 与糖尿病和低磷酸化Rb过度表达有关。 初步数据表明，当Rh过度表达时，肾脏和 系膜细胞肥大进一步在糖尿病条件下。我们假设 解释这些观察结果是过量的葡萄糖导致特定的， 细胞周期蛋白依赖的Rb蛋白磷酸化在早期Gi期， Rb参与肾小球系膜细胞肥大的远端通路。 为了验证这一假设，提出了三个具体目标：（1）确定 糖尿病是否在体内引起肾脏和肾小球肥大 和离体高糖浓度引起的系膜细胞肥大 依赖于特定的C1期细胞周期蛋白-cdk复合物的激活， Rb蛋白的特异性磷酸化。(2)确定血糖有多高 调节肾小球系膜细胞中cdk 4-cyclin D1活性和Rb磷酸化， 检查基因调控模式，包括细胞周期蛋白D1的转录 基因本身和相关转录因子控制的事件 包括AP-1。(3)检测对Cl细胞周期蛋白依赖性激酶的要求 Rb蛋白的活化和特异性cdk 4依赖性磷酸化， 体内糖尿病性肾肥大和培养的系膜细胞肥大。 Rb关键磷酸化位点失活的转基因小鼠 将产生定点突变，1型糖尿病的影响 将在其中检查糖尿病。原代系膜细胞也将被 从小鼠培养和更详细的研究肥大和胃肠道细胞 体外研究cdks和Rb对细胞周期的调节作用。

项目成果

Nek1 regulates cell death and mitochondrial membrane permeability through phosphorylation of VDAC1.

• DOI: 10.4161/cc.8.2.7551
• 发表时间: 2009-01-15
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Chen Y;Craigen WJ;Riley DJ
• 通讯作者: Riley DJ

Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control.

• DOI: 10.4161/cc.7.20.6815
• 发表时间: 2008-10
• 期刊: CELL CYCLE
• 影响因子: 4.3
• 作者: Chen, Yumay;Chen, Phang-Lang;Chen, Chi-Fen;Jiang, Xianzhi;Riley, Daniel J.
• 通讯作者: Riley, Daniel J.

Aberrant DNA damage response and DNA repair pathway in high glucose conditions.

• DOI: 10.6000/1929-2279.2018.07.03.1
• 发表时间: 2018-06
• 期刊: Journal of cancer research updates
• 作者: Amy Zhong;Melissa H Y Chang;T-H Yu;Raymond Gau;D. Riley;Yumay Chen;Phang-lang Chen

Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1.

NEK1磷酸化调节电压依赖性阴离阴离子通道1的打开和关闭。

• DOI: 10.1016/j.bbrc.2010.03.077
• 发表时间: 2010-04-09
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Chen, Yumay;Gaczynska, Maria;Osmulski, Pawel;Polci, Rosaria;Riley, Daniel J.
• 通讯作者: Riley, Daniel J.

Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability.

• DOI: 10.1186/1476-4598-10-5
• 发表时间: 2011-01-10
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Chen Y;Chen CF;Chiang HC;Pena M;Polci R;Wei RL;Edwards RA;Hansel DE;Chen PL;Riley DJ
• 通讯作者: Riley DJ