Use of small molecules that stabilize dynamin rings in podocytopathies

在足细胞病中使用稳定动力环的小分子

基本信息

批准号：
8258352
负责人：
Sanja Sever
金额：
$ 37.16万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8258352
关键词：
Accounting Actinin Actins Adaptor Signaling Protein Adriamycin PFS Affect Animal Model Applications Grants Binding Biological Preservation Cathepsin L Cell membrane Cells Chronic Kidney Failure Clathrin Complex Cytoplasm Cytoskeleton Data Disease Down-Regulation Dynamin End stage renal failure Endocytosis Endocytosis Inhibition Epidemic Focal Adhesions Foot Process Functional disorder Genetic Genetic Models Goals Guanosine Triphosphate Phosphohydrolases Higher Order Chromatin Structure Integral Membrane Protein Kidney Kidney Diseases Laboratory Study Life Mediating Modeling Mus Nephrosis Nephrotic Syndrome Peptide Hydrolases Pharmaceutical Preparations Play Process Proteinuria Proteolysis Puromycin Aminonucleoside Rattus Regulation Resources Rodent Model Role Series Signal Transduction Stress Fibers Structure Testing Transgenic Mice Ultrafiltration United States Work base efficacy testing gain of function insight mouse model mutant nephrin neuronal cell body novel novel therapeutics podocyte prevent public health relevance restoration slit diaphragm small molecule

项目摘要

DESCRIPTION (provided by applicant): The global epidemic of chronic kidney disease is progressing at an alarming rate. In the United States alone, glomerular kidney diseases affect some 20 million people, and this number has roughly doubled in the last two decades. Indeed, kidney-related diseases are rapidly eluding present treatment options and resources. Thus, it is high priority to uncover novel therapeutics to treat chronic kidney diseases. Podocytes are specialized cells within the glomerulus that are essential for kidney ultrafiltration. They form foot processes (FPs), highly dynamic actin-based cellular extensions that are connected by slit diaphragms. Most forms of proteinuria and nephrotic syndrome are characterized by transformation of podocyte FPs into a band of cytoplasm due to de- regulation of the actin cytoskeleton (referred to as FP effacement). The work in this proposal is based on our recent identification of the GTPase dynamin as a major regulator of actin dynamics in podocytes. Studies from this laboratory suggest that preservation of dynamin function is sufficient to reverse FP effacement, restore functional podocytes and ameliorate proteinuria. We have recently shown that dynamin directly regulates the actin cytoskeleton in podocytes. In addition, we have identified small molecules that promote dynamin oligomerization into rings, which in turn protects actin cytoskeleton in podocytes. In this grant application we test the ability of dynamin ring stabilizer drugs to reverse FP effacement and ameliorate proteinuria in different rodent models of proteinuric kidney disease. In Specific Aim 1 we test efficacy of dynamin drugs in inducible models of proteinuric kidney disease such as a rat model of puromycin aminonucleoside (PAN) nephrosis and a rat model of adriamycin nephrosis. In Specific Aim 2 we test efficacy of dynamin ring stabilizer drugs in genetic models of proteinuric kidney diseases such as (1) mouse model in which actin cytoskeleton is mis- regulated due to expression of 'gain of function' 1-actinin 4 mutant; (2) mice lacking CD2AP (adaptor protein involved in regulation of actin cytoskeleton and signaling in podocytes); (3) transgenic mice expressing high levels of TGF-¿1. In Specific Aim 3 we examine whether ring stabilizing drugs effect turnover of the nephrin at the plasma membrane. Our work has potential to identify dynamin drugs as novel therapeutics to treat proteinuric kidney diseases. PUBLIC HEALTH RELEVANCE: In the United States alone, glomerular type of kidney diseases effects some 20 million people, and this number has roughly doubled within the last two decades. Here we propose to test the ability of subset of small molecules (drugs) that specifically target GTPase dynamin to ameliorate proteinuria by restoring podocyte structure and function. Different drugs will be tested in inducible and genetic rodent models of proteinuric kidney diseases.

描述（由适用提供）：慢性肾脏疾病的全球流行正在以惊人的速度进展。仅在美国，肾小球肾脏疾病就会影响约2000万人，在过去的二十年中，这个数字大约增加了一倍。确实，与肾脏有关的疾病正在迅速避免目前的治疗选择和资源。这是很高的优先事项，可以发现新的治疗慢性肾脏疾病的疗法。足细胞是肾小球内的专门细胞，对于肾脏超滤至关重要。它们形成脚步工艺（FPS），基于肌动蛋白的高度动态肌动蛋白扩展，这些扩展是通过缝隙拨号连接的。大多数形式的蛋白尿和肾病综合征的特征是由于肌动蛋白细胞骨架的去调控（称为FP能量），将足细胞FPS转化为细胞质带。该提案中的工作基于我们最近将GTPase Dynamin作为足细胞肌动蛋白动力学的主要调节剂的鉴定。该实验室的研究表明，动力蛋白功能的保存足以逆转FP效率，恢复功能性足细胞和改善蛋白尿。我们最近表明，动力蛋白直接调节足细胞中的肌动蛋白细胞骨架。此外，我们已经确定了促进动力蛋白寡聚成环的小分子，这反过来又保护了肌动蛋白细胞骨架。在此赠款应用中，我们测试了动力蛋白环稳定剂药物在蛋白尿肾脏疾病的不同啮齿动物模型中逆转FP能量和改善蛋白尿的能力。在特定目标1中，我们在蛋白尿肾脏疾病的诱导模型中测试了动力蛋白药物的效率，例如嘌呤霉素氨核苷（PAN）肾脏症的大鼠模型和adriamycin肾脏症的大鼠模型。 2我们在蛋白尿肾脏疾病的遗传模型中测试动力蛋白环稳定剂药物的有效性，例如（1）小鼠模型，其中肌动蛋白细胞骨架由于“功能获得的增长” 1-肌动蛋白4突变体而受到调控。（2）缺乏CD2AP的小鼠（与肌动蛋白细胞骨架调节和足细胞中的信号传导有关的衔接蛋白）；（3）表达高水平TGF-€1的转基因小鼠。在特定目标3中，我们检查了环稳定药物是否影响质膜处肾素的离职。我们的工作有可能鉴定动力蛋白药物作为治疗蛋白尿肾脏疾病的新疗法。公共卫生相关性：仅在美国，肾小球类型的肾脏疾病会影响约2000万人，而在过去的二十年中，这个数字大约增加了一倍。在这里，我们建议通过恢复足细胞结构和功能来测试特异性靶向GTPase dynamin来改善蛋白尿的小分子（药物）子集的能力。在蛋白尿肾脏疾病的诱导和遗传啮齿动物模型中将测试不同的药物。