Multi-level analysis of iron metabolism and treatment of chronic kidney disease

描述（由申请人提供）：慢性肾脏疾病（Chronic kidney disease， CKD）以轻度至重度贫血为特征，伴有严重的病理后果。静脉注射铁和促红细胞生成素（Epo）联合透析治疗CKD患者贫血，可显著改善治疗效果。由于缺乏铁和促生成素剂量的定量信息，以及重组促生成素的高成本，阻碍了最佳治疗。此外，过量的铁会使患者暴露于心脏损伤，可能是由铁引起的自由基氧化损伤。我们的研究计划的长期目标是开发一种全身铁代谢的预测模型，该模型将利用最近和持续的对铁运输机制的遗传学和细胞生物学的理解。该模型有望为CKD患者的个性化治疗提供定量的、基于机制的指导，以最大限度地提高铁补充剂的疗效和减少有害的副作用。我们将采用系统生物学的方法，在实验的设计和分析中使用数学建模和模拟。我们的方法跨越了不同的研究领域，需要一个经验丰富的研究团队，在实验生物学，计算建模和医学方面具有专业知识。我们在这个应用程序的所有主要方面组建了一个由公认的专家组成的独特多学科团队。该团队由细胞和分子生物学家（Paul Fox博士，P.I.）和具有复杂生物系统数学建模专业知识的生物医学工程师（Gerald Saidel博士，Co-I）领导。他们在铁代谢的实验和计算/建模方面有着长期的兴趣。我们团队的其他重要成员是：Saul Nurko医学博士，CKD贫血治疗方面的肾病专家，Linda Graham医学博士，血管外科医生，改善了小鼠CKD的手术模型，Alan Lichtin医学博士和Roy Silverstein医学博士，分别是造血疾病和细胞生物学治疗方面的血液学家，以及Marc Penn医学博士，心脏生理学和衰竭方面的心脏病专家。我们的团队是高度整合的，参与者之间有多种互动。我们的模型将独特地利用铁转运蛋白的动力学特性，而不是以前的基于扩散的模型。该全身模型将用于制定CKD贫血的最佳治疗方案。这些方案将在小鼠CKD手术模型中进行体内试验。对心脏的不良影响将通过心脏铁积累、心功能和肥厚来衡量。这项工作的潜在影响非常大。一个预测的、基于机制的全身铁代谢数学模型将为小肠、骨髓、肝脏和骨髓等关键铁稳态系统之间的相互作用提供可测试的见解。此外，该模型可以为未来的临床医生提供CKD（以及潜在的其他贫血）的个性化治疗工具，可以优化红细胞生成，最小化成本，最重要的是，减少心脏肥厚和心力衰竭等不良副作用。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is characterized by mild to severe anemia with severe pathological consequences. Treatment of anemia in CKD patients by intravenous injection of iron and erythropoietin (Epo) in combination with dialysis, significantly improves results. Optimal treatment is hampered by the lack of quantitative information on iron and Epo dosage, and by the high cost of recombinant Epo. Moreover, excess iron exposes the patient to cardiac injury, presumably by iron-induced, free radical oxidative damage. The long- term goal of our research program is to develop a predictive model of whole-body iron metabolism that will take advantage of recent and continuing advances in understanding the genetics and cell biology of iron transport mechanisms. The model is expected to provide quantitative, mechanism-based guidance for personalized treatment of patients with CKD to maximize efficacy and minimize injurious side-effects of iron supplements. We will take a systems biology approach in which mathematical modeling and simulation is used in the design and analysis of experiments. Our approach spans diverse research areas and necessitates an experienced research team with expertise in experimental biology, computational modeling, and medicine. We have assembled a unique multidisciplinary team of recognized experts in all major aspects of this application. The team is led by a cell and molecular biologist (Paul Fox, Ph.D., P.I.) and by a biomedical engineer with specific expertise in mathematical modeling of complex biological systems (Gerald Saidel, Ph.D. Co-I). They share long-standing interest in experimental and computational/modeling aspects of iron metabolism. The other essential members of our team are: Saul Nurko, M.D., a nephrologist with expertise in treatment of CKD anemia, Linda Graham, M.D., a vascular surgeon who has improved the surgical model of CKD in the mouse, Alan Lichtin, M.D. and Roy Silverstein, M.D., hematologists with expertise in treatment of hematopoietic disease and cell biology, respectively, and Marc Penn, M.D., Ph.D., a cardiologist with expertise in heart physiology and failure. Our team is highly integrated with multiple interactions among the participants. Our model will uniquely take advantage of the kinetic characteristics of iron transport proteins as opposed to previous diffusion-based models. The whole-body model will be used to develop optimal treatment regimens for the anemia of CKD. The regimens will be tested in vivo in a surgical model of CKD in mice. Adverse effects on the heart will be measured as cardiac iron accumulation and cardiac function and hypertrophy. The potential impact of this work is very high. A predictive, mechanism-based mathematical model of whole-body iron metabolism will provide testable insights into the interactions between the key iron homeostatic systems - the small intestine, bone marrow, liver, and marrow. Moreover, this model can provide future clinicians with a tool for personalized treatment of CKD (and potentially other anemias) that can optimize erythropoiesis, minimize cost, and most importantly, reduce adverse side-effects such as cardiac hypertrophy and failure. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) patients are generally afflicted with mild to severe anemia, which can lead to heart failure and other cardiovascular disorders. The anemia-related symptoms of kidney disease are improved by treatment with the hormone erythropoietin and iron, but their beneficial effect on heart disease is controversial, and recent studies show increased risk of heart disease upon over-treatment. We have assemble a unique multidisciplinary research team of scientists and clinicians, with expertise in kidney and heart disease, cell biology, iron metabolism, systems biology, and mathematical modeling. Our goal is to investigate the mechanisms regulating iron homeostasis during of CKD, and devise regimens for personalized treatment that will improve health and minimize risk.