CAREER: Multiscale Modeling of a Virtual Kidney during the Onset and Progression of Diabetic Kidney Disease

职业：糖尿病肾病发病和进展过程中虚拟肾脏的多尺度建模

• 批准号: 2133411
• 负责人: Ashlee Ford Versypt
• 金额: $ 55万
• 依托单位: SUNY at Buffalo
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2133411&HistoricalAwards=false
• 关键词: CAREER; Multiscale; Modeling; Virtual; Kidney

Diabetic kidney disease (DKD) is a serious complication of both type 1 and type 2 diabetes and is the leading cause of kidney failure. Yet, it is still not clear how the many underlying chemical, physical, and biological processes interact to damage the kidneys during diabetes. It is challenging to monitor the damage to the kidneys inside a patient. The regions of the kidney that are damaged are very small and are deep within the body. It takes a long time for irreversible damage to accumulate to the point where non-invasive urine samples contain detectable quantities of proteins that leaked through the kidneys. This Faculty Early Career Development Program (CAREER) project will connect several processes that have been shown individually to contribute to injury in kidneys due to diabetes into a sophisticated computer simulation. This computational tool will aid in understanding how the processes interact and how diabetic kidney damage begins and changes over time. In the long-term, results from this project will help to predict the impacts of many competing factors on kidney health during diabetes management. The computer simulation produced in the project can also be used to test and optimize treatments to slow the progression of DKD. The project also will involve a set of educational activities related to the scientific work. Several undergraduate and graduate students including women and underrepresented minorities will work with the PI to conduct the research and educational activities. Educational modules related to the research will be delivered to a variety of groups including K-12 students, college students, and grandparents. Physical models of kidney tissues will be 3D-printed and shared with students and educators. The activities will expose many students and members of the public to biomedical engineering and computational science through engaging scientific demonstrations and interactive experiences.The principal investigator's long-term career goal is to develop multiscale computational models to enhance understanding of the mechanisms governing tissue remodeling and damage as a result of diseases and infections and to simulate the treatment of those conditions to improve human health. Toward this goal, this project will develop a novel computational approach for studying diabetic kidney disease (DKD) through a virtual kidney that can be used like a powerful, non-invasive microscope to look into the body to detect and monitor damage to the glomeruli (where most damage occurs) during the onset and progression of diabetic complications in the kidney. The virtual kidney platform will use multiscale computational modeling to connect effects at different length scales from smaller to larger: inside cells, between adjacent cells, across a single glomerulus, and among collections of glomeruli interacting with other tissues in a kidney. A hybrid computational approach will take advantage of the benefits of stochastic differential equations to describe chemical species that react and interact in large quantities and of agent-based models to describe cells and chemical species that interact in small quantities or in qualitative up- or down-regulation fashions. The Research Plan is organized under two aims. The FIRST AIM is to formulate cellular level mathematical models of biochemical cell signaling networks responsible for damage in each of the three main glomerular zones: a) podocytes, b) mesangial cells and mesangial matrix and c) endothelial cells and the glomerular basement membrane. Computational tools will be developed for importing biochemical networks, conducting uncertainty and sensitivity analyses, and validating model results for the three zones. To assess validity, computational models will be compared to experimental evidence gleaned from the literature. The SECOND AIM is to build a virtual kidney computational model focusing on crosstalk, structural, and hemodynamic effects on the primary tissue compartments within multiple nephrons. Steps include: a) constructing a hybrid computational model for tissue level simulation of glomerular cells that combines information from reactions in single cells, connects multiple interacting cells and transports glucose and other molecules through the mesangium and the glomerular filtration barrier; b) connecting the glomerular models to a tubule and vessel centric-model for blood flow and filtration regulation and c) validating the virtual kidney model and simulating responses to stimuli. A user-friendly interface will be created for specifying model input and stimuli, running the simulations, and visualizing results. Simulations of the virtual kidney model will be rigorously compared to pharmacological, physiological, and histological data, primarily from humans. After model validation to a subset of the data cases, in silico experiments will be conducted to predict the magnitudes and rates of change for glomerular injury outcomes including proteinuria and glomerular filtration rate (GFR) under DKD pathophysiological conditions. The metric for success will be the accurate simulation of the classic trajectory of onset and progression of DKD subject to clinically relevant input and stimuli. Computational tools and code developed will be distributed openly via GitHub repositories, which may be of broad interest to the systems biology research community using SBML and/or CompuCell3D. In summary, the project addresses the critical need to compile the multiple mechanistic processes that contribute to DKD onset and progression into a user-friendly systematic framework capable of taking the interconnected chemical, physical, and biological factors into account in a coupled fashion and in the appropriate magnitudes and sequences to make testable predictions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

糖尿病肾病（DKD）是1型和2型糖尿病的严重并发症，是肾衰竭的主要原因。然而，目前尚不清楚许多潜在的化学、物理和生物过程是如何相互作用而损害糖尿病患者的肾脏的。监测病人体内肾脏的损伤是一项挑战。肾脏受损的区域非常小，并且位于身体深处。不可逆转的损害需要很长时间才能积累到非侵入性尿液样本中含有可检测到的蛋白质并通过肾脏泄漏的程度。这个教师早期职业发展计划（Career）项目将把几个被单独证明会导致糖尿病肾脏损伤的过程连接到一个复杂的计算机模拟中。这个计算工具将有助于理解这些过程是如何相互作用的，以及糖尿病肾损害是如何开始和随时间变化的。从长远来看，该项目的结果将有助于预测糖尿病管理期间许多竞争因素对肾脏健康的影响。该项目中产生的计算机模拟也可用于测试和优化减缓DKD进展的处理方法。该项目还将包括一系列与科学工作相关的教育活动。包括妇女和代表性不足的少数民族在内的一些本科生和研究生将与PI合作开展研究和教育活动。与该研究相关的教育模块将提供给包括K-12学生、大学生和祖父母在内的各种群体。肾脏组织的物理模型将被3d打印，并与学生和教育工作者共享。这些活动将通过参与科学演示和互动体验，使许多学生和公众接触到生物医学工程和计算科学。首席研究员的长期职业目标是开发多尺度计算模型，以加强对疾病和感染导致的组织重塑和损伤的控制机制的理解，并模拟这些条件的治疗，以改善人类健康。为了实现这一目标，该项目将开发一种新的计算方法，通过一个虚拟肾脏来研究糖尿病肾病（DKD），这个虚拟肾脏可以像一个强大的、非侵入性的显微镜一样，在肾脏糖尿病并发症的发生和发展过程中，检测和监测肾小球的损伤（肾小球损伤最多的地方）。虚拟肾脏平台将使用多尺度计算建模来连接不同长度尺度的效应，从小到大：细胞内，相邻细胞之间，单个肾小球之间，以及肾小球与肾脏中其他组织相互作用的集合。混合计算方法将利用随机微分方程的优势来描述大量反应和相互作用的化学物质，以及基于主体的模型来描述少量或定性的上下调节模式的细胞和化学物质。研究计划有两个目标。第一个目标是建立在三个主要肾小球区域(a)足细胞，b)系膜细胞和系膜基质，c)内皮细胞和肾小球基底膜)中负责损伤的生化细胞信号网络的细胞水平数学模型。将开发计算工具，用于导入生化网络，进行不确定性和敏感性分析，并验证三个区域的模型结果。为了评估有效性，将计算模型与从文献中收集的实验证据进行比较。第二个目标是建立一个虚拟肾脏计算模型，重点关注多个肾单位内主要组织室的串扰、结构和血流动力学影响。步骤包括：a)构建用于组织水平肾小球细胞模拟的混合计算模型，该模型结合单个细胞的反应信息，连接多个相互作用的细胞，并通过系膜和肾小球滤过屏障运输葡萄糖和其他分子；B)将肾小球模型连接到小管和血管中心模型，用于血液流动和过滤调节；c)验证虚拟肾脏模型并模拟对刺激的反应。将创建一个用户友好的界面，用于指定模型输入和刺激，运行模拟和可视化结果。虚拟肾脏模型的模拟将与主要来自人类的药理学、生理学和组织学数据进行严格比较。在对一部分数据病例进行模型验证后，将进行计算机实验，以预测DKD病理生理条件下肾小球损伤结果（包括蛋白尿和肾小球滤过率（GFR））的变化幅度和速率。成功的标准将是准确模拟DKD在临床相关输入和刺激下的发病和进展的经典轨迹。计算工具和开发的代码将通过GitHub存储库公开发布，这可能会引起使用SBML和/或CompuCell3D的系统生物学研究社区的广泛兴趣。总之，该项目解决了将导致DKD发生和发展的多种机制过程汇编成一个用户友好的系统框架的关键需求，该框架能够以耦合的方式考虑相互关联的化学、物理和生物因素，并以适当的幅度和顺序进行可测试的预测。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Multiscale modeling in disease

• DOI: 10.1016/j.coisb.2021.05.001
• 发表时间: 2021-05
• 期刊: Current opinion in systems biology
• 影响因子: 3.7
• 作者: Ashlee N. Ford Versypt

Numerical Problem Solving across the Curriculum with Python and MATLAB Using Interactive Coding Templates: A Workshop for Chemical Engineering Faculty

使用交互式编码模板通过 Python 和 MATLAB 跨课程解决数值问题：化学工程教师研讨会

• 发表时间: 2023
• 期刊: Proceedings of the ASEE Annual Conference
• 作者: Johns, Austin N.;Hesketh, Robert P.;Stuber, Matthew D.;Ford Versypt, Ashlee N.
• 通讯作者: Ford Versypt, Ashlee N.

Collagen Deposition in Diabetic Kidney Disease Boosts Intercellular Signaling: A Mathematical Model

糖尿病肾病中的胶原蛋白沉积增强细胞间信号传导：数学模型

• DOI: 10.1016/j.ifacol.2023.01.017
• 发表时间: 2022
• 期刊: IFAC-PapersOnLine
• 作者: Thomas, Haryana Y.;Versypt, Ashlee N.
• 通讯作者: Versypt, Ashlee N.

Kidney and Lung Demonstrations to Introduce Engineering Concepts to Middle School Students and Their Grandparents

肾脏和肺脏演示，向中学生及其祖父母介绍工程概念

• 发表时间: 2021
• 期刊: Proceedings of the ASEE Annual Conference
• 作者: Ford Versypt, A. N.;Carpenter, S. L.;Adkins, T. L.;Sperry, T. A.;Feng, Y.
• 通讯作者: Feng, Y.