Hemopexin as an Early Biomarker of Anthracycline Cardiac Toxicity

血红素结合蛋白作为蒽环类药物心脏毒性的早期生物标志物

基本信息

批准号：
10593077
负责人：
Aarti Asnani
金额：
$ 65.43万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593077
关键词：
Address Adriamycin PFS Affinity Algorithms Anthracycline Binding Biodistribution Biological Biological Assay Biological Markers Blood Brain Breast Cancer therapy Cancer Biology Cardiac Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Chemicals Chronic Clinical Collaborations Cytotoxic Chemotherapy Data Dedications Diagnosis Dose Doxorubicin Drug Metabolic Detoxication Echocardiography Enzyme-Linked Immunosorbent Assay Female Genetic Glycoproteins Hand Heart Heart Injuries Heart failure Hematologic Neoplasms Heme Hemopexin Human Imaging Techniques Inflammation Inflammatory Institution Investigation Iron Iron Overload Israel Kinetics Knockout Mice Liver Lymphoma Macrophage Malignant Neoplasms Measures Mediating Medical center Metabolism Molecular Mus Myocardial dysfunction Natriuretic Peptides Oncology Oxidative Stress Pathogenesis Pathway interactions Patients Phenotype Physiological Pilot Projects Plasma Plasma Proteins Prognosis Proteins Proteomics Reactive Oxygen Species Recycling Reticuloendothelial System Risk Rodent Model Role Spleen Stress Toxic effect Treatment Protocols Troponin Validation Wild Type Mouse Woman Work aptamer biobank biomarker identification cancer therapy cardioprotection chemotherapy cohort cost effective early detection biomarkers effective therapy heart function heme oxygenase-1 heme-binding protein improved insight iron metabolism leukemia loss of function male malignant breast neoplasm medical schools mouse model multidisciplinary novel therapeutic intervention patient population prevent professor receptor mediated endocytosis response risk stratification sarcoma screening trend

项目摘要

PROJECT SUMMARY This project seeks to contribute new insights into the role of heme metabolism in the pathogenesis of anthracycline cardiac toxicity by leveraging studies in human patients and mouse models. The project will be led by Aarti Asnani, MD, Cardiologist and Director of Cardio-Oncology at Beth Israel Deaconess Medical Center (BIDMC) and Assistant Professor at Harvard Medical School (HMS). Dr. Asnani will collaborate with a multidisciplinary team that will provide expertise in heme and cancer biology. Anthracyclines such as doxorubicin (Dox) are very effective chemotherapies, but their use is limited by cardiac toxicity. Current risk stratification and cardioprotective strategies are inadequate in patients treated with anthracyclines, largely because they do not reflect the underlying molecular mechanisms of toxicity. To address this unmet need, we used aptamer-based proteomics to measure over 1,300 plasma proteins in a discovery cohort of women treated with anthracyclines for breast cancer. In addition to changes in proteins previously associated with anthracycline cardiomyopathy, we identified hemopexin (HPX) as a new biomarker of cardiac toxicity, findings that were validated in a second patient cohort using an ELISA-based assay. HPX is a 57-kDa circulating glycoprotein synthesized in the liver that has a high binding affinity for the iron-containing molecule heme, which is pro-oxidant and inflammatory. Upon binding to heme, HPX undergoes receptor-mediated endocytosis via LRP-1, which is expressed by circulating macrophages and enables heme recycling in the splenic reticuloendothelial system. This heme detoxification pathway is largely mediated by intracellular heme oxygenase-1. Intracellular iron overload and macrophage-mediated inflammation have been described as key molecular mechanisms of Dox cardiac toxicity, underscoring the biological plausibility of HPX as a biomarker in this setting. Motivated by these human findings, we used a mouse model of chronic doxorubicin cardiomyopathy to assess the mechanistic implications of HPX induction in anthracycline cardiac toxicity. Based on our preliminary findings, we hypothesize that HPX is not only a biomarker of cardiac toxicity, but also a cardioprotective pathway that is activated in response to anthracyclines. We will address this hypothesis in the following aims: (1) To characterize the effects of HPX gain and loss-of-function on cardiac phenotypes in a mouse model of chronic Dox cardiomyopathy; (2) To define the role of HPX in Dox cardiac toxicity through integrative analyses of HPX kinetics and biodistribution, heme/iron metabolism, and chemical and genetic HO- 1 modulation; and (3) To assess the generalizability of blood heme, HPX, and other mechanistic biomarkers of cardiac toxicity in diverse patient populations treated with anthracyclines. In addition to establishing HPX as a biomarker of anthracycline cardiac toxicity, this line of investigation will clarify the role of heme metabolism in cardiovascular disease more broadly. Modulation of HPX and associated pathways could ultimately represent a new therapeutic strategy to protect the heart during chemotherapy.

项目摘要该项目旨在为血红素代谢在发病机理中的作用做出新的见解通过利用人类患者和小鼠模型的研究，蒽环心脏的心脏毒性。该项目将是由Aarti Asnani，心脏病专家Aarti Asnani领导，贝丝以色列执事医学主任中心（BIDMC）和哈佛医学院（HMS）的助理教授。 Asnani博士将与多学科团队将提供血红素和癌症生物学专业知识。蒽环类药物等阿霉素（DOX）是非常有效的化学疗法，但其使用受心脏毒性的限制。当前风险在接受蒽环类药物治疗的患者中，分层和心脏保护策略不足，在很大程度上因为它们不反映毒性的潜在分子机制。为了满足这个未满足的需求，我们使用基于适应性的蛋白质组学在发现女性中测量超过1300个血浆蛋白用蒽环类药物治疗乳腺癌。除了先前与 Anthracycline心肌病，我们确定血压素（HPX）是心脏毒性的新生物标志物使用基于ELISA的测定法在第二个患者队列中进行了验证。 HPX是一个57 kDa循环在肝脏中合成的糖蛋白对含铁分子血红素具有高结合亲和力，促氧化剂和炎症。与血红素结合后，HPX经历受体介导的内吞作用通过LRP-1，通过循环巨噬细胞表达并在脾脏中启用血红素回收网状内皮系统。该血红素排毒途径在很大程度上是由细胞内血红素介导的氧酶-1。细胞内铁超载和巨噬细胞介导的炎症已被描述为关键 DOX心脏毒性的分子机制，强调了HPX作为生物标志物的生物学合理性此设置。由这些人类发现的动机，我们使用了慢性阿霉素的小鼠模型心肌病评估HPX诱导在蒽环类心脏毒性中的机理意义。根据我们的初步发现，我们假设HPX不仅是心脏毒性的生物标志物，而且是响应于蒽环类药物而激活的心脏保护途径。我们将在以下目的：（1）表征HPX增益和功能丧失对A中心脏表型的影响慢性DOX心肌病的小鼠模型；（2）通过通过 HPX动力学和生物分布，血红素/铁代谢以及化学和遗传性的综合分析 1个调制；（3）评估血红素，HPX和其他机械生物标志物的普遍性用蒽环类药物治疗的多样化患者种群的心脏毒性。除了确定HPX作为一个蒽环类心脏毒性的生物标志物，这种研究线将阐明血红素代谢在心血管疾病更广泛。 HPX和相关途径的调节最终可以表示在化学疗法期间保护心脏的一种新的治疗策略。