Mechanisms of Hydroxyurea Efficacy in Sickle Cell Disease

羟基脲治疗镰状细胞病的疗效机制

基本信息

批准号：
9983149
负责人：
Aisha Lanette Walker
金额：
$ 14.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9983149
关键词：
Address Adult Alternative Therapies Award Biological Assay Birth CD34 gene Caring Carnitine Cations Cell Culture Techniques Cell membrane Cells Clinical Communication Data Development Disease Educational process of instructing Ensure Environment Erythrocytes Erythroid Erythroid Cells Erythropoiesis FDA approved Fetal Development Fetal Hemoglobin Functional disorder Gene Expression Gene Expression Regulation Globin Goals Hematological Disease Hematology Hemoglobin concentration result Hospitalization Human In Vitro Inherited Knowledge Leadership Learning Mediating Medical Membrane Transport Proteins Mentors Mentorship MicroRNAs Modeling Molecular Analysis Molecular Target Mus Neonatal Outcome Pathology Patients Pharmaceutical Preparations Pharmacogenetics Pharmacology Pharmacotherapy Production Professional Competence Program Development Publishing Refractory Regulation Research Research Personnel Research Project Grants Role Sampling Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Technical Expertise Testing Time Training Transduction Gene Transgenic Mice Transgenic Organisms Translational Research United States Universities Viral Genes Work base career career development cost drug action gain of function gamma Globin hydroxyurea improved in silico in vitro Assay in vitro Model in vivo in vivo Model interest loss of function mortality mouse model new therapeutic target novel novel therapeutics polymerization progenitor response skills stem cells uptake urea transporter

项目摘要

PROJECT SUMMARY Sickle cell disease (SCD) is one of the most commonly inherited blood disorders world-wide with an annual cost of over 1 billion dollars in the United States alone. Currently, there is only one FDA-approved drug for managing SCD, hydroxyurea (HU). HU efficacy is attributed largely to augmented expression of gamma-globin in erythroid progenitors leading to increased production of fetal hemoglobin to ameliorate many complications of SCD. However, the increase in fetal hemoglobin may not be sufficient for some patients, and they may not benefit this therapy for reasons that are unknown. With limited alternative therapies available there is a need to improve efficacy of HU and develop new drugs for these patients. This project will provide new information about the mechanisms of HU efficacy that can offer pharmacogenetic targets to help personalize HU therapy and offer new therapeutic targets of fetal hemoglobin induction for developing additional treatments for SCD. Its novel concepts combined with a detailed training plan and mentorship from a highly accomplished team of translational and clinical researchers will also facilitate the career development of the principle investigator. Our previous work investigating modulators of HU pharmacology has identified that the cell membrane transporters urea transporter B (UTB) and organic cation/carnitine transporter1 (OCTN1) regulate the intracellular accumulation of HU. These transporters govern how much drug reaches intracellular targets and are associated with augmented fetal hemoglobin levels. We also found that intracellular miRNAs, miR- 148a, - 151-3p, and -494 are associated with HU therapy in erythroid cells of sickle cell patients in association with increased fetal hemoglobin level. Thus, we have identified two potential mechanisms through which HU may elicit an increase in fetal hemoglobin levels. To date, model limitations have hindered our studies to investigate these modulators in an in vivo model of SCD. Given these previous findings, we hypothesize that induction of fetal hemoglobin by hydroxyurea is modulated by transporters and miRNAs. In the rich research environment at University of Pittsburgh, using an in vitro model of erythropoiesis, we will test our hypothesis in the following two aims: 1) to determine whether UTB and OCTN1 transporters control uptake and efficacy of HU to induce fetal hemoglobin and 2) to determine whether miR-148a, -151-3p, and -494 control the efficacy HU to induce fetal hemoglobin. In a third aim, we will develop a novel in vivo model to dissect these and other mechanisms of hydroxyurea-mediated fetal hemoglobin in SCD. While conducting the translational research, the candidate will also take classes, participate in career development programs, learn technical skills in viral gene transduction and improve professional competencies related to communication, mentoring, teaching, management and leadership. Throughout the project mentoring by a team of senior-level hematology and stem cell researchers will help ensure that the candidate launches an independent research career and realize the long-term goal of improving treatment for SCD.

项目摘要镰状细胞病（SCD）是全球最常见的血液疾病之一，年度仅在美国，成本就超过10亿美元。目前，只有一种FDA批准的药物管理SCD，羟基脲（HU）。 HU功效主要归因于γ-球蛋白的增强表达在红细胞祖细胞中，导致胎儿血红蛋白产生增加以改善许多并发症 SCD。但是，胎儿血红蛋白的增加可能不足以适合某些患者，并且可能不足出于未知原因而受益于这种疗法。有限的替代疗法可用提高HU的功效并为这些患者开发新药。该项目将提供新信息关于HU功效的机制，可以提供药物遗传靶标以帮助个性化HU治疗并提供胎儿血红蛋白诱导的新治疗靶标，以开发SCD的其他治疗方法。它的新颖概念结合了一支高度成就的团队的详细培训计划和指导翻译和临床研究人员还将促进主要研究人员的职业发展。我们以前研究的HU药理学调节剂已经确定了细胞膜转运蛋白尿素转运蛋白B（UTB）和有机阳离子/carnitine Transporter1（Octn1）调节 HU的细胞内积累。这些转运蛋白控制着多少药物达到细胞内靶标，并且与增强的胎儿血红蛋白水平有关。我们还发现细胞内miRNA，mir -148a， - 151-3p和-494与镰状细胞患者的红细胞细胞中的HU治疗有关胎儿血红蛋白水平升高。因此，我们已经确定了HU可以通过的两种潜在机制引起胎儿血红蛋白水平的升高。迄今为止，模型限制阻碍了我们的研究来调查这些调节剂在SCD的体内模型中。鉴于这些先前的发现，我们假设羟基脲胎儿血红蛋白由转运蛋白和miRNA调节。在丰富的研究环境中在匹兹堡大学，使用红细胞生成的体外模型，我们将在下面测试我们的假设两个目的：1）确定UTB和OCTN1转运蛋白是否控制HU的摄取和功效胎儿血红蛋白和2）确定miR -148a，-151-3p和-494是否控制疗效HU以诱导胎儿血红蛋白。在第三个目标中，我们将开发一种新颖的体内模型来剖析这些和其他机制 SCD中的羟基脲介导的胎儿血红蛋白在进行翻译研究时，候选人还将上课，参加职业开发计划，学习病毒基因转导技术技能并提高专业能力与沟通，指导，教学，管理和领导力有关。在整个项目指导中由高级血液学和干细胞研究人员组成的团队将有助于确保候选人推出独立的研究职业，并实现改善SCD治疗的长期目标。