Understanding kidney physiology: Modeling and analysis

当肾脏缺氧时，可能会发生缺氧(低血氧)，随后可能会出现慢性肾脏疾病。尽管进行了密集的研究，但肾脏缺氧的机制仍然知之甚少。这种困难可能是由于构成肾脏综合功能基础的数百万个肾小管(肾单位)和血管之间的复杂相互作用，但这一点仍有待充分表征。-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)开发一个详细的大鼠肾脏综合功能计算模型，并使用该模型来检查肾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丢失的模拟，以确定必须保留或抑制哪些必要的肾单位结构和功能，以增加肾脏脆弱部分的氧平衡，同时维持整体肾功能？(2)模拟并深入了解肾脏缺氧的发展和影响。模型模拟将被用来研究影响肾组织氧分压的因素，特别是在脆弱的外髓，包括Na+转运到更远和更低效的肾单位段，氧化应激升高，超滤和肾小管肥大。我们将模拟和研究不同手法的有效性，并回答以下问题：如何在限制对其他肾功能的影响的同时增加钠的排泄(由高血压治疗引起)，并保持氧合？降压动作在多大程度上增加了肾脏的氧分压并保护了器官？(3)开发和应用计算模型来分析肾功能的性别差异。最近的实验研究发现，啮齿动物肾脏的肾单位存在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肾功能的关键决定因素的洞察，以及肾脏转运蛋白的突变如何影响肾功能和电解质动态平衡。该奖项支持的受训人员将学习肾脏生理学、计算模型和数值方法。

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.