Flow-stimulated endocytosis in the proximal tubule

近端小管中的流动刺激内吞作用

基本信息

批准号：
8969601
负责人：
Ora A Weisz
金额：
$ 34.05万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969601
关键词：
Actins Acute Albumins Animal Model Apical Blood Volume Cell Line Cells Chronic Chronic Kidney Failure Cilia Clathrin Cystinosis Data Defect Development Dextrans Diabetes Mellitus Disease Disease Pathway Endocytosis Enzymes Equilibrium Filtration Glomerular Filtration Rate Health Homeostasis Hormones Human In Situ Individual Injury Ion Transport Ions Kidney Kidney Diseases Kidney Failure LDL-Receptor Related Protein 2 Lead Ligands Link Liquid substance Mediating Molecular Molecular Weight Mus Neurons Oculocerebrorenal Syndrome PKD2 protein Pathogenesis Pathway interactions Patients Phase Phosphatidylinositols Phosphoric Monoester Hydrolases Plasma Play Proteins Proteinuria Proximal Kidney Tubules Recovery Renal function Research Research Personnel Role Signal Transduction Site Sodium-Hydrogen Antiporter Surface Testing Therapeutic Intervention Translating Tubular formation Urine Vitamins Water Wiskott-Aldrich Syndrome Zebrafish blood pressure regulation cilium biogenesis coated pit combat density extracellular improved insight interest intrinsic factor-cobalamin receptor kidney cell knock-down metal poisoning mouse model novel receptor research study response shear stress small molecule solute therapy design uptake

项目摘要

DESCRIPTION (provided by applicant): The proximal tubule (PT) of the kidney is the primary site for reabsorption of ions, solutes, and filtered low molecular weight (LMW) proteins. PT cells acutely modulate ion transport capacity in respond to changes in fluid shear stress (FSS) that accompany alterations in glomerular filtration rate. This proposal is focused on understanding whether PT cells also adjust the capacity of megalin-and cubilin- mediated endocytosis of LMW proteins in response to altered demand. Defective uptake of these proteins leads to tubular proteinuria, which can eventually lead to renal failure. We have discovered that apical endocytosis of the megalin/cubilin ligand albumin as well as fluid phase markers is markedly increased upon exposure of PT cells to FSS. Moreover, primary cilia are required for this response. The aims of this proposal are to (1) determine how changes in FSS are transduced into effects on apical endocytosis and (2) determine whether defective modulation of flow-dependent endocytosis contributes to LMW proteinuria observed in animal models for Lowe Syndrome, an X- linked disorder that may involve defects in ciliogenesis. We have assembled an outstanding team of investigators with essential expertise to carry out this broad range of studies. The results of our experiments will provide key information about a newly discovered pathway that plays an essential role in maintaining kidney function.

描述（由申请人提供）：肾脏的近端小管（PT）是使离子，溶质和过滤的低分子量（LMW）蛋白重吸收的主要部位。 PT细胞急性调节离子运输能力，响应伴随肾小球滤过速率改变的流体剪应力（FSS）变化。该提案的重点是了解PT细胞是否还可以调整LMW蛋白的梅加林和Cubilin介导的内吞作用的能力，以应对需求的改变。这些蛋白质的缺陷摄取导致肾小管蛋白尿，最终会导致肾衰竭。我们已经发现，在PT细胞暴露于FSS时，Megalin/Cubilin配体白蛋白以及流体相位标记的根尖内吞作用明显增加。此外，此响应需要主要的纤毛。该提案的目的是（1）确定FSS的变化如何转化为对根尖内吞作用的影响，并且（2）确定流动依赖性内吞作用的有缺陷调节是否有助于LMW蛋白尿在Lowe综合征中观察到的LMW蛋白尿，这是一种可能涉及ciliewoess的X链接疾病，这可能涉及X-连接的疾病。我们组建了一个杰出的调查员团队，具有重要的专业知识，以进行这项广泛的研究。我们的实验结果将提供有关新发现的途径的关键信息，该途径在维持肾脏功能中起着至关重要的作用。