Role of dynamin oligomerization in podocyte structure and function

动力寡聚化在足细胞结构和功能中的作用

• 批准号: 9097196
• 负责人: Sanja Sever
• 金额: $ 37.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097196
• 关键词: Accounting; Actins; Affect; Animal Model; Applications Grants; Biological Preservation; Cell membrane; Cell physiology; Cells; Chronic Kidney Failure; Clathrin; Collagen Type IV; Complex; Cytoplasm; Cytoskeleton; Data; Deposition; Diabetic Nephropathy; Disease; Dynamin; End stage renal failure; Endocytosis; Endothelial Cells; Epidemic; Eukaryota; Fluorescence Microscopy; Focal Adhesions; Foot Process; Functional disorder; Funding; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Injury; Kidney; Kidney Diseases; Label; Laboratory Study; Ligands; Mediating; Medicine; Membrane; Membrane Protein Traffic; Modeling; Molecular; Nature; Nephrotic Syndrome; Obese Mice; Pharmaceutical Preparations; Plasma; Play; Process; Property; Proteinuria; Publishing; Rattus; Regulation; Resources; Rodent Model; Role; Signal Transduction; Signal Transduction Pathway; Site; Stress Fibers; Structure; Testing; Ultrafiltration; United States; Work; base; extracellular; glomerular function; mesangial cell; mouse model; nephrin; novel; novel therapeutics; parent grant; podocyte; polymerization; public health relevance; slit diaphragm; small molecule

 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 a 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 fot processes (FPs), highly dynamic actin-based cellular extensions that are connected by slit diaphragms. Most forms of proteinuria and nephrotic syndromes are characterized by the transformation of podocyte FPs into bands of cytoplasm due to dysregulation 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 shown that dynamin directly regulates the actin cytoskeleton in podocytes. In addition, we have identified small molecule that promotes dynamin oligomerization into rings, which in turn protects the actin cytoskeleton in podocytes. We have recently shown that administration of dynamin-specific small molecule reversed FP effacement and ameliorated proteinuria in diverse animal models of chronic kidney diseases. Originally, we focused on the role of dynamin in regulating the actin cytoskeleton in podocytes. In this grant application we expand our original observation by focusing on the role that dynamin-actin interaction, dynamin oligomerization, and dynamin-specific molecules play in regulating clathrin-mediated endocytosis. Endocytosis is a key process in all eukaryotes by which portions of the plasma membrane, along with extracellular material, are internalized. It plays an essential role in regulating signaling pathwas that originate at the plasma membrane. In Specific Aim 1 we investigate the role that dynamin plays in regulating actin-dependent endocytosis in podocytes. In Specific Aim 2 we investigate whether endocytosis plays a role during crosstalk between podocytes and glomerular endothelial cells. In Specific Aim 3 we investigate whether actin-dependent endocytosis plays a role in reversing early signs of glomerular injury such as mesangial matrix expansion and deposition of collagen IV by examining the effects of dynamin-specific small molecules in rodent models of progressive kidney injury.

 描述（由申请人提供）：慢性肾病的全球流行正在以惊人的速度发展。仅在美国，肾小球肾病就影响了大约 2000 万人，并且这个数字在过去二十年中大约增加了一倍。事实上，与肾脏相关的疾病正在迅速摆脱现有的治疗选择和资源。因此，发现治疗慢性肾脏疾病的新疗法是当务之急。足细胞是肾小球内的特殊细胞，对于肾脏超滤至关重要。它们形成叶突（FP），即通过狭缝隔膜连接的基于肌动蛋白的高度动态的细胞延伸。大多数蛋白尿和肾病综合征的特征是由于肌动蛋白细胞骨架失调（称为 FP 消失），足细胞 FP 转化为细胞质带。本提案中的工作基于我们最近确定的 GTP 酶动力作为足细胞肌动蛋白动力学的主要调节因子。该实验室的研究表明，保留动力功能足以逆转 FP 消失、恢复足细胞功能并改善蛋白尿。我们已经证明，动力直接调节足细胞中的肌动蛋白细胞骨架。此外，我们还发现了促进动力蛋白寡聚成环的小分子，从而保护足细胞中的肌动蛋白细胞骨架。我们最近表明，在多种慢性肾病动物模型中，给予动力蛋白特异性小分子可逆转 FP 消失并改善蛋白尿。最初，我们关注的是动力在调节足细胞肌动蛋白细胞骨架中的作用。在这项拨款申请中，我们通过关注动力蛋白-肌动蛋白相互作用、动力寡聚化和动力特异性分子在调节网格蛋白介导的内吞作用中所起的作用来扩展我们最初的观察。内吞作用是所有真核生物的一个关键过程，通过该过程，部分质膜以及细胞外物质被内化。它在调节起源于质膜的信号通路中起着重要作用。在具体目标 1 中，我们研究了动力蛋白在调节足细胞肌动蛋白依赖性内吞作用中的作用。在具体目标 2 中，我们研究了内吞作用是否在足细胞和肾小球内皮细胞之间的串扰过程中发挥作用。在具体目标 3 中，我们通过检查动力蛋白特异性小分子在进行性肾损伤啮齿动物模型中的作用，研究肌动蛋白依赖性内吞作用是否在逆转肾小球损伤的早期症状（例如系膜基质扩张和 IV 型胶原蛋白沉积）中发挥作用。