Understanding kidney physiology: Modeling and analysis

当肾脏缺氧时，可发生缺氧（低血氧），并可能随之发生慢性肾脏疾病。尽管进行了大量的研究，但对肾性缺氧途径的机制仍然知之甚少。这种困难可能是由于数以百万计的肾小管（肾单位）和血管之间复杂的相互作用，形成肾脏综合功能的基础，但仍有待充分表征。基于我的团队在开发代表复杂相互作用的大鼠肾脏计算模型方面的专业知识，我们将扩展这些模型并进行以下研究活动：(1)开发综合大鼠肾脏功能的详细计算模型，并使用该模型来检查肾脏功能和髓质氧合的关键决定因素。将进行基因敲除和肾单位损失的模拟，以确定：在维持肾脏整体功能的同时，必须保留或抑制哪些必要的肾单位结构和功能来增加肾脏易损部分的氧平衡？(2)模拟并了解肾性缺氧的发生发展及其影响。将进行模型模拟以研究影响肾组织氧张力的因素，特别是在脆弱的外髓质，包括Na+转运到更远端和效率较低的肾元段的转移、氧化应激升高、超滤和肾小管肥大。我们将模拟和研究不同操作的有效性，并回答以下问题：如何增加钠排泄（由高血压治疗引起），同时限制对其他肾脏功能的影响并保持氧合？降血压运动在多大程度上增加肾氧张力并保护器官？(3)建立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啮齿动物肾脏肾元沿线令人惊讶和重要的性别差异。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，以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，钠和水是血压设定点的关键决定因素。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。所提出的计算模型的独特之处在于，它们在不同的生物尺度上纳入了肾脏运输和代谢过程，并且它们代表了肾功能的性别差异。我们的研究计划的长期目标是寻求对肾功能的关键决定因素的见解，以及肾转运蛋白的突变如何影响肾功能和电解质稳态。该奖项支持的学员将学习肾脏生理学、计算建模和数值方法。

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.