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: 9918332
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918332
• 关键词: Actins; Affect; Animal Model; Applications Grants; 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; Histologic; Injury; Injury to Kidney; Kidney; Kidney Diseases; Label; Laboratory Study; Ligands; Mediating; Medicine; Membrane; Modeling; Molecular; Nature; Nephrotic Syndrome; Obese Mice; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Process; Property; Proteinuria; Publishing; Regulation; Resources; Rodent Model; Role; Signal Transduction; Signal Transduction Pathway; Site; Stress Fibers; Structure; Testing; Ultrafiltration; United States; Work; alpha Actin; base; diabetic rat; extracellular; glomerular endothelium; glomerular function; mesangial cell; mouse model; nephrin; novel; novel therapeutics; parent grant; podocyte; polymerization; preservation; 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(申请人提供)：慢性肾脏疾病的全球流行正在以惊人的速度发展。仅在美国，肾小球疾病就影响了大约2000万人，这个数字在过去20年里大约翻了一番。事实上，与肾脏相关的疾病正在迅速避开目前的治疗选择和资源。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，对肾脏超滤至关重要。它们形成FOT突起(FP)，这是一种高度动态的基于肌动蛋白的细胞延伸，由狭缝横隔膜连接。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失调(称为FP消失)，足细胞FP转化为细胞质条带。这项建议中的工作是基于我们最近发现的GTPase Dynamin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，动力蛋白功能的保留足以逆转FP的消失，恢复功能性足细胞，并改善蛋白尿。我们已经证明，动力素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，这反过来又保护足细胞中的肌动蛋白细胞骨架。我们最近已经证明，在不同的慢性肾脏疾病动物模型中，动力蛋白特异性小分子的应用逆转了FP的消失，并改善了蛋白尿。最初，我们专注于Dynamin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，我们通过重点研究动力蛋白-肌动蛋白相互作用、动力蛋白寡聚作用和动力蛋白特异性分子在调节网状蛋白介导的内吞作用中所起的作用，扩展了我们最初的观察。内吞作用是所有真核生物中的一个关键过程，通过这个过程，质膜的一部分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至关重要的作用。在特定目标1中，我们研究了Dynamin在调节足细胞肌动蛋白依赖的内吞作用中所起的作用。在特定的目标2中，我们研究内吞作用是否在足细胞和肾小球内皮细胞之间的串扰中起作用。在具体目标3中，我们通过检测动力蛋白特异性小分子在进行性肾损伤动物模型中的作用，研究肌动蛋白依赖的内吞作用是否在逆转肾小球损伤的早期迹象中发挥作用，如肾小球系膜基质扩张和IV型胶原沉积。

项目成果

Podocyte biology and pathogenesis of kidney disease.

• DOI: 10.1146/annurev-med-050311-163340
• 发表时间: 2013
• 期刊: Annual review of medicine
• 影响因子: 10.5
• 作者: Reiser J;Sever S
• 通讯作者: Sever S

Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases.

• DOI: 10.1016/j.kint.2017.12.028
• 发表时间: 2018-06
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Sever S;Schiffer M
• 通讯作者: Schiffer M

Role of actin cytoskeleton in podocytes.

• DOI: 10.1007/s00467-020-04812-z
• 发表时间: 2021-09
• 期刊: Pediatric nephrology (Berlin, Germany)
• 作者: Sever S

Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease.

• DOI: 10.1038/nm.4242
• 发表时间: 2017-01
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Hahm E;Wei C;Fernandez I;Li J;Tardi NJ;Tracy M;Wadhwani S;Cao Y;Peev V;Zloza A;Lusciks J;Hayek SS;O'Connor C;Bitzer M;Gupta V;Sever S;Sykes DB;Scadden DT;Reiser J
• 通讯作者: Reiser J