权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结