Understanding kidney physiology: Modeling and analysis

了解肾脏生理学：建模和分析

• 批准号: RGPIN-2019-03916
• 负责人: Layton, Anita
• 金额: $ 6.11万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714520
• 关键词: Understanding; kidney; physiology; Modeling; analysis

When the kidneys are deprived of oxygen, hypoxia (low blood oxygen) can occur and chronic kidney diseases may follow. Despite intense research, the mechanisms that underlie the pathways to renal hypoxia remain poorly understood. That difficulty may be due to the complex interplay among the millions of renal tubules (nephrons) and vessels that forms the basis for the integrative function of the kidney but that remains to be fully characterized. Building on my team's expertise in developing computational models of the rat kidney that represent the complex interactions, we will extend those models and conduct the following research activities: (1) To develop a detailed computational model of integrative rat kidney function, and to use that model to examine key determinants of kidney function and medullary oxygenation. Simulations of gene knockout and nephron loss will be conducted to determine: What are the necessary nephron structures and functions that must be preserved or inhibited to increase oxygen balance in the vulnerable parts of the kidney, while maintaining overall kidney functions? (2) To simulate and gain insights into the development and impacts of renal hypoxia. Model simulations will be conducted to investigate factors that impact kidney tissue oxygen tension, particularly in the vulnerable outer medulla, including shift in Na+ transport to the more distal and less efficient nephron segments, elevated oxidative stress, hyperfiltration, and tubular hypertrophy. We will simulate and investigate the effectiveness of differing maneuvers and answer questions: How can one increase sodium excretion (motivated by hypertension treatment) while limiting effects on other kidney functions and preserve oxygenation? To what extent do blood pressure reduction maneuvers increase kidney oxygen tension and protect the organ? (3) To develop and apply computational models to analyze sex differences in kidney function. Recent experimental studies have revealed surprising and important sex-based differences along the nephron of the rodent kidney. To analyze that data, we will develop sex-specific computational models and conduct simulations to better understand sex differences in kidney function. In particular, we will study the differences in which male and female rats handle sodium and water, the key determinants of blood pressure set point. Our research program is novel in its use of computational modeling and simulations to study kidney function. The proposed computational models are unique in that they incorporate renal transport and metabolic processes at different biological scales, and that they represent sex differences in kidney function. The long-term goals of our research program are to seek insights into the key determinants of kidney function, and into how mutations in renal transporters affect kidney function and electrolyte homeostasis. Trainees supported by this award would have learned renal physiology, computational modeling, and numerical methods.

当肾脏 缺氧、缺氧(低血氧)可发生慢性肾功能不全 疾病可能随之而来。尽管进行了密集的研究，但支持 肾脏缺氧的途径仍然知之甚少。这一困难可能是由于 数以百万计的肾小管(肾单位)和 构成肾脏整体功能基础的血管，但 这一点还有待于充分说明。 基于我的团队在开发代表复杂结构的大鼠肾脏计算模型方面的专业知识 交互，我们将扩展这些模型并执行以下操作 研究活动： (1)发展 完整大鼠肾功能的详细计算模型，并使用 该模型用于检查肾功能和骨髓氧合的关键决定因素。 将进行基因敲除和肾单位丢失的模拟，以确定： 必须保留的必要的肾单位结构和功能是什么 或被抑制以增加肾脏脆弱部分的氧平衡， 在维持整体肾功能的同时？ (2)模拟 并深入了解肾脏缺氧的发展和影响。型号 将进行模拟以调查影响肾组织的因素 氧紧张，特别是在脆弱的外髓，包括Na+转移到更远和效率较低的肾单位节段，氧化应激升高，高滤过和肾小管肥大。我们将模拟和研究不同方案的有效性 动作和回答问题：如何增加钠的排泄 (受高血压治疗的激励)，同时限制对其他肾脏的影响 功能和维持氧合？血压下降到什么程度？ 动作增加肾脏氧分压并保护器官？ (三)大力发展 并应用计算模型分析肾功能的性别差异。最近的实验研究揭示了令人惊讶和重要的基于性的 啮齿动物肾脏沿肾单位的差异。为了分析这些数据，我们 将开发针对性别的计算模型并进行模拟 更好地了解肾功能的性别差异。特别是，我们将 研究雄性和雌性大鼠处理钠和水的差异， 血压设定值的关键决定因素。 我们的研究项目在使用计算建模和模拟来研究肾功能方面是新颖的。所提出的计算模型是独一无二的，因为它们包含了不同生物尺度上的肾脏运输和代谢过程，并且它们代表了肾功能的性别差异。 我们研究计划的长期目标是寻求对关键决定因素的洞察 肾功能以及肾脏转运蛋白突变如何影响肾脏 功能和电解质动态平衡。获得该奖项支持的学员将 学习了肾脏生理学、计算模型和数值方法。