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

描述（由申请方提供）：慢性肾脏疾病（CKD）的特征是轻度至重度贫血，伴有严重的病理后果。通过静脉注射铁和促红细胞生成素（Epo）联合透析治疗CKD患者的贫血，显著改善了结果。最佳的治疗受到铁和EPO剂量的定量信息的缺乏，以及重组EPO的高成本的阻碍。此外，过量的铁使患者暴露于心脏损伤，可能是由铁诱导的自由基氧化损伤。我们研究计划的长期目标是开发一个全身铁代谢的预测模型，该模型将利用最近和持续的进展来理解铁转运机制的遗传学和细胞生物学。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，以最大限度地提高疗效并最大限度地减少铁补充剂的有害副作用。我们将采用系统生物学方法，其中数学建模和模拟用于实验的设计和分析。我们的方法跨越不同的研究领域，需要一个经验丰富的研究团队，具有实验生物学，计算建模和医学方面的专业知识。我们已经组建了一个独特的多学科团队，由该应用的所有主要方面的公认专家组成。该团队由细胞和分子生物学家（Paul Fox博士，P.I.）以及在复杂生物系统的数学建模方面具有特定专业知识的生物医学工程师（Gerald Saidel，Ph.D. Co-I）。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：扫罗努尔科，医学博士，琳达格雷厄姆，医学博士，一位血管外科医生，他改进了小鼠CKD的手术模型，罗伊·西尔弗斯坦医学博士分别在造血系统疾病和细胞生物学治疗方面具有专长的血液学家和Marc Penn，M.D.，博士，心脏病专家，擅长心脏生理学和衰竭。我们的团队高度整合，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。全身模型将用于开发CKD贫血的最佳治疗方案。将在小鼠CKD手术模型中对方案进行体内测试。对心脏的不良影响将被测量为心脏铁积累和心脏功能和肥大。这项工作的潜在影响非常大。一个预测性的、基于机制的全身铁代谢数学模型将为关键的铁稳态系统（小肠、骨髓、肝脏和骨髓）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用于CKD（以及潜在的其他贫血）的个性化治疗的工具，其可以优化红细胞生成，最小化成本，并且最重要的是，减少不良副作用，例如心脏肥大和衰竭。 公共卫生相关性：慢性肾病（CKD）患者通常患有轻度至重度贫血，这可能导致心力衰竭和其他心血管疾病。肾脏疾病的贫血相关症状通过激素促红细胞生成素和铁的治疗得到改善，但它们对心脏病的有益作用是有争议的，最近的研究表明，过度治疗会增加心脏病的风险。我们组建了一支由科学家和临床医生组成的独特的多学科研究团队，他们在肾脏和心脏病，细胞生物学，铁代谢，系统生物学和数学建模方面具有专业知识。我们的目标是研究CKD期间铁稳态的调节机制，并设计个性化治疗方案，以改善健康状况并将风险降至最低。

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.