Red blood cell modifiers for Plasmodium falciparum growth in sickle cell disease erythrocytes

用于镰状细胞病红细胞中恶性疟原虫生长的红细胞修饰剂

• 批准号: 10224189
• 负责人: Natasha Marie Bernadette Archer
• 金额: $ 16.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10224189
• 关键词: Advisory Committees; Affect; Africa; Area; Award; Binding; Biological Assay; Boston; Cell Cycle; Cell Cycle Stage; Cells; Cellular Assay; Cellular biology; Cessation of life; Child; Communities; Coupled; DNA biosynthesis; Data; Digestion; Disease; Disease Outcome; Epidemiology; Erythrocytes; Falciparum Malaria; Fetal Hemoglobin; Foundations; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Growth; Hemoglobin; Hemoglobin C; Hemoglobin F Disease; Hemoglobin SC Disease; Hemoglobinopathies; Heterozygote; Hypoxia; In Vitro; Individual; Infection; Inherited; Institution; Integration Host Factors; International; Leadership; Malaria; Maps; Mathematics; Mediating; Mentors; Modeling; Molecular; Morbidity - disease rate; Mutate; Mutation; Newborn Infant; Outcome; Oxygen; Parasitemia; Parasites; Pathology; Patients; Pediatric Hematologist; Pediatric Hematology; Pediatric Hospitals; Phenotype; Physicians; Plasmodium falciparum; Ploidies; Point Mutation; Population; Positioning Attribute; Proliferating; Public Health Schools; Research; Research Personnel; Research Proposals; Research Training; Resistance; Role; Scientist; Severities; Sickle Cell Anemia; Sickle Hemoglobin; Staging; Structure; Subgroup; Testing; Thalassemia; Therapeutic; Training; Transgenic Organisms; Umbilical Cord Blood; Virulence; Virulent; Work; alpha-Thalassemia; career; cell type; clinically relevant; comorbidity; experience; genome sequencing; hemoglobin AA; improved; in vivo Model; malaria infection; mathematical model; mortality; novel; parasite genome; polymerization; premature; programs; resistant Plasmodium falciparum; reverse genetics; sickling; skills; therapeutic target

PROJECT SUMMARY/ABSTRACT Sickle cell disease (SCD) is a deadly red blood cell (RBC) disorder estimated to affect over 300,000 newborns annually1. In SCD, mutated hemoglobin (HbS) polymerizes2 and causes RBCs to become sickle- shaped. SCD remains prevalent because heterozygous carriers (HbAS) are partially resistance to Plasmodium falciparum malaria3,4, which causes 400,000 deaths annually5. I recently identified HbS polymerization in low oxygen (O2) as the main driver in HbAS resistance to P. falciparum6. This should suggest homozygous HbSS confers greater resistance to malaria, but paradoxically, infected SCD individuals (HbSS) have increased malaria morbidity and mortality7-9. I propose a novel hypothetical model of SCD and malaria interaction in which RBC factors, like fetal hemoglobin (HbF), that create a RBC reservoir in which little to no HbS polymerization occurs, may enable severe malaria. Using a variety of SCD RBC cell types, I will map and model the in vitro growth dynamics of P. falciparum in SCD erythrocytes and identify RBC factors that influence malaria infectivity within this population. This work is foundational in elucidating the molecular mechanisms underlying the interaction between SCD and malaria, and is a major first step in identifying novel treatment targets for severe malaria, SCD, and its comorbidities. I am a pediatric hematologist co-mentored by Dr. Manoj Duraisingh and Dr. Caroline Buckee, both of Harvard's T.H. Chan School of Public Health. My long-term goal is to become an independent physician- scientist investigating the effect of the RBC host on malaria growth and to target such factors therapeutically. My prior research experiences have allowed me to acquire the cellular biology skills to investigate in vitro malaria growth. Through the critical mentored K08 award, I am now well positioned to acquire new skills in mathematical modeling and parasite genetics to better understand the epidemiology of hemoglobinopathies in malaria endemic regions, assess the impact of the introduction of RBC polymorphisms within communities, and find potential therapeutic targets for children with SCD that become infected with malaria. The Boston Children's Hospital and Harvard T.H. Chan School of Public Health are internationally recognized research programs with a number of expert researchers in the areas of hemoglobinopathies, mathematical modeling, and malaria. Boston Children's Hospital, my primary institution, has a distinguished record of training young physician-scientists for leadership roles in pediatric hematology research. I have assembled an excellent scientific advisory committee, consisting of Drs. Higgins, Goldberg, and Sankaran. Drs. Brugnara and Nathan, will continue to serve as my career mentors and guide my research and training experiences. With the structured mentoring, educational, and research plans detailed in this proposal, I will acquire the necessary expertise to become a successful independent investigator with a focus on hemoglobinopathies and malaria.

项目摘要/摘要 镰状细胞病（SCD）是一种致命的红细胞（RBC）疾病，估计会影响超过30万 每年新生儿1。在SCD中，突变的血红蛋白（HBS）聚合2，并导致RBC成为镰状 - 形状。 SCD仍然普遍存在，因为杂合载体（HBA）部分抗性疟原虫 恶性疟疾3,4，每年造成400,000人死亡5。我最近确定了低点的HBS聚合 氧（O2）是HBAS抗性恶性疟原虫6的主要驱动因素。这应该建议纯合HBSS 赋予对疟疾的更大抵抗力，但自相矛盾的是，受感染的SCD个体（HBS）增加了 疟疾发病率和死亡率7-9。我提出了一种新型的SCD和疟疾相互作用的假设模型 RBC因胎儿血红蛋白（HBF）等因素而产生了RBC储层，其中几乎没有HBS 聚合发生，可能会导致严重的疟疾。使用各种SCD RBC单元类型，我将映射和 对SCD红细胞中恶性疟原虫的体外生长动力学进行建模，并鉴定影响影响的RBC因子 该人群中的疟疾感染性。这项工作是阐明分子机制的基础 SCD和疟疾之间的相互作用是基本的，并且是识别新治疗的主要第一步 严重疟疾，SCD及其合并症的目标。 我是由Manoj Duraisingh博士和Caroline Buckee博士共同注册的儿科血液学家 哈佛大学陈公共卫生学院。我的长期目标是成为一名独立的医生 - 科学家研究了RBC宿主对疟疾生长的影响，并以治疗性靶向此类因素。 我先前的研究经验使我能够获得细胞生物学技能来研究体外 疟疾生长。通过关键指导的K08奖，我现在有能力获得新的技能 数学建模和寄生虫遗传学，以更好地了解血红蛋白病的流行病学 疟疾流行地区，评估RBC多态性在社区中引入的影响， 并为患有疟疾感染的SCD儿童找到潜在的治疗靶标。波士顿 儿童医院和哈佛T.H.陈公共卫生学院是国际公认的研究 与许多专家研究人员有关血红蛋白病，数学建模的计划， 和疟疾。波士顿儿童医院是我的小学机构，有着杰出的培训记录 医师科学家在儿科血液学研究中发挥领导作用。我组装了一个很好的 科学咨询委员会，由Drs组成。希金斯，戈德堡和桑卡兰。博士。 Brugnara和Nathan， 将继续担任我的职业导师，并指导我的研究和培训经验。与 结构化指导，教育和研究计划详细介绍了我将获得必要的 专业知识成为一名成功的独立研究者，专注于血红蛋白病和疟疾。