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.

抽象的 肾功能障碍会导致严重的医疗状况，包括蛋白尿，骨质疏松症和 肾结石的形成。这些情况更频繁地发生，并且在机组人员中进展更快 驻扎在国际空间站。当前的近端和远端管的静态模型是 无法概括细胞功能，包括通过梅加林，维生素D代谢的蛋白质重吸收 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物生理模型 使用原代细胞上皮细胞（PTEC）成功证明的近端细胞上皮细胞（PTEC） 生理细胞结构/极化，葡萄糖和药物底物的转运，无活性25-的生物活化 羟基维生素D至1α，25-二羟基维生素D（促进有益的骨重塑）和生理 对有毒暴露的伤害反应。我们将扩展这项技术以开发远端细胞上皮细胞 模型（DTEC）将用于探索对草酸盐微晶体的病理生理反应。 在国际空间站的微重力环境中研究近端和远端小管 提出了观察加速疾病过程的独特机会（蛋白尿，骨质疏松症，肾脏 石头），这将有助于发现有助于发展和发展的因素 无法在常规时间尺度上观察到的肾脏疾病。因此，该项目的目的是： 确定微重力对极化结构方面（例如离子和可溶性转运蛋白）的影响 3D微生物生理系统中的肾脏近端和远端小节上皮，以确定维生素D是否是否 肾脏近端小管内的生物活化/体内稳态，以响应延长的暴露而受到损害 进行微重力，并创建近端细胞蛋白尿和远端小节肾脏的疾病状态模型 石材形成以评估微重力的有害或自适应调节作用。 更好地理解基于适当的细胞结构和发展的因素和途径 肾脏疾病的进展将发现可用于发育的新型治疗靶标 可以改善空间站工作人员健康的药理学剂以及 公众通过预防或逆转蛋白尿，骨质疏松症和肾结石。