Effects of microgravity on the structure and function of proximal and distal tubule MPS

微重力对近远曲小管MPS结构和功能的影响

• 批准号: 9890028
• 负责人: Jonathan Himmelfarb
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890028
• 关键词: 3-Dimensional; Address; Adenosine Triphosphate; Adverse effects; Biological; Biological Sciences; Bone remodeling; Calcium; Calcium Oxalate; Carrier Proteins; Cell Polarity; Cell model; Cell physiology; Cellular Structures; Chemical Exposure; Chronic; Clinic; Collaborations; Critical Pathways; Crystallization; Dehydration; Development; Diabetic Nephropathy; Dietary Sodium; Dietary intake; Dihydroxycholecalciferols; Disease; Disease Pathway; Disease Progression; Disease susceptibility; Distal; Distal convoluted renal tubule structure; Electrolytes; Environment; Epithelial; Epithelial Cells; Epithelium; Exposure to; Fat-Soluble Vitamin; Force of Gravity; Functional disorder; General Population; Glucose; Glucose Transporter; Goals; Gravitation; Health; Henle' s loop; Homeostasis; Individual; International; Ions; Kidney; Kidney Calculi; Kidney Diseases; Knowledge; LDL-Receptor Related Protein 2; Maintenance; Mediating; Medical; Medical emergency; Metabolic; Microgravity; Modeling; Nephritis; Nephrons; Osteoporosis; Osteoporosis prevention; Oxalates; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Planet Earth; Potassium; Prevention; Process; Proteins; Proteinuria; Proximal Kidney Tubules; Recycling; Research Design; Research Support; Risk; Salts; Serum Proteins; Sodium; Space Flight; Structure; System; Technology; Time; Toxicant exposure; Toxin; Tubular formation; Universities; Urine; Vitamin D; Washington; Water; bone; design; environmental chemical; experience; glucose transport; improved; innovation; kidney dysfunction; microphysiology system; new therapeutic target; novel; organ on a chip; peptide drug; prevent; protein transport; response; response to injury; small molecule; solute; space station; uptake; urinary; water conservation

Abstract Kidney dysfunction can precipitate serious medical conditions including proteinuria, osteoporosis, and formation of kidney stones. These conditions occur more frequently, and progress faster, in crewmembers stationed on the International Space Station. Current static models of the proximal and distal tubules are unable to recapitulate cellular functions including protein reabsorption via megalin, vitamin D metabolic bioactivation, and micro-crystal mediated injury response. We have developed a microphysiologic model of the proximal tubule using primary proximal tubule epithelial cells (PTECs) that has successfully demonstrated physiologic cellular structure/polarization, transport of glucose and drug substrates, bioactivation of inactive 25- hydroxy vitamin D to 1α,25-dihydroxyvitamin D (which promotes beneficial bone remodeling), and physiologic injury response to toxic exposure. We will expand this technology to develop a distal tubule epithelial cell model (DTEC) which will be used to explore the pathophysiologic response to oxalate microcrystals. Studying the proximal and distal tubules in the microgravity environment of the International Space Station presents the unique opportunity to observe accelerated disease processes (proteinuria, osteoporosis, kidney stones), which will facilitate the discovery of factors that contribute to the development and progression of kidney diseases that cannot be observed on a conventional time scale. Therefore, the aims of this project are: to determine the effects of microgravity on the polarized structural aspects (eg., ion and solute transporters) of the kidney proximal and distal tubule epithelium in a 3D microphysiological system, to determine if Vitamin D bioactivation/homeostasis within the kidney proximal tubule is compromised in response to extended exposure to microgravity, and to create a disease-state models of proximal tubule proteinuria and distal tubule kidney stone formation to evaluate the harmful or adaptive modulating effects of microgravity. A better understanding of the factors and pathways that underlie proper cellular structure and the development and progression of kidney diseases will uncover novel therapeutic targets that can be used in the development of pharmacologic agents that can improve the health of Space Station crewmembers as well as the health of the general public by preventing or reversing proteinuria, osteoporosis, and kidney stones.

摘要 肾功能不全可导致严重的医疗状况，包括蛋白尿、骨质疏松症和糖尿病。 肾结石的形成这些情况在机组人员中发生得更频繁，进展更快 驻扎在国际空间站上。目前近端和远端小管的静态模型是 无法重现细胞功能，包括通过巨蛋白重吸收蛋白质，维生素D代谢 生物活化和微晶介导的损伤反应。我们已经开发了一个微生理模型， 使用原代近曲小管上皮细胞（PTECs）的近曲小管，已成功证明 生理细胞结构/极化，葡萄糖和药物底物的转运，无活性25- 羟基维生素D到1α，25-二羟基维生素D（促进有益的骨重建），以及生理性 对毒性暴露的损伤反应。我们将扩大这项技术，开发一种远端小管上皮细胞， 模型（DTEC），将用于探索草酸盐微晶的病理生理反应。 在国际空间站的微重力环境中研究近端和远端小管 提供了观察加速疾病过程（蛋白尿、骨质疏松症、肾脏疾病）的独特机会。 这将有助于发现有助于发展和进步的因素， 在传统的时间尺度上无法观察到的肾脏疾病。因此，该项目的目标是： 为了确定微重力对极化结构方面的影响（例如，离子和溶质转运蛋白） 肾脏近端和远端小管上皮细胞在3D微生理系统，以确定是否维生素D 肾脏近端小管内的生物活化/体内平衡因长期暴露而受损 建立了近端小管蛋白尿和远端小管肾脏的疾病状态模型 结石形成，以评估微重力的有害或适应性调节效应。 更好地了解构成适当细胞结构和发育基础的因素和途径， 肾脏疾病的进展将发现新的治疗靶点， 这些药物可以改善空间站机组人员的健康， 通过预防或逆转蛋白尿、骨质疏松症和肾结石，