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

摘要 肾功能障碍可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。这些情况在船员中发生得更频繁，进展也更快。 驻扎在国际空间站。目前近端和远端小管的静态模型为 无法概括细胞功能，包括通过巨蛋白、维生素D代谢进行蛋白质重吸收 生物激活和微晶体介导的损伤反应。我们已经开发了一种微生理学模型 利用原代近端小管上皮细胞(PTECs)成功地证明了近端小管 生理细胞结构/极化，葡萄糖和药物底物的运输，非活性25- 羟基维生素D至1α，25-二羟基维生素D(促进有益的骨骼重塑)和生理学 对有毒物质暴露的伤害反应。我们将扩展这项技术以开发远端小管上皮细胞 模型(DTEC)，将被用来探索草酸盐微晶的病理生理反应。 国际空间站微重力环境中近端和远端小管的研究 提供了观察加速疾病过程(蛋白尿、骨质疏松症、肾脏)的独特机会 石头)，这将有助于发现有助于发展和进展的因素 无法在常规时间尺度上观察到的肾脏疾病。因此，这个项目的目标是： 确定微重力对极化结构方面(例如，离子和溶质转运体)的影响 3D微生理系统中的肾脏近端和远端小管上皮细胞，以确定维生素D 肾脏近端小管内的生物激活/动态平衡因长期暴露而受损 建立近端肾小管蛋白尿和远端肾小管疾病状态模型 以评估微重力的有害或适应性调节效果。 更好地了解构成适当细胞结构和发育的因素和途径 肾脏疾病的进展将揭示可用于开发的新的治疗靶点 可以改善空间站工作人员健康以及空间站工作人员健康的药理药物 预防或逆转蛋白尿、骨质疏松症和肾结石。

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.