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

项目摘要/摘要 镰状细胞病(SCD)是一种致命的红细胞(RBC)疾病，估计影响超过30万人 每年一次的新生儿。在SCD中，突变的血红蛋白(HBS)聚合，并导致红细胞变成镰刀状. 很有型。SCD仍然流行，因为杂合子携带者(HbA)对疟疾有部分抵抗力 恶性疟疾3，4，每年造成40万人死亡5。我最近在Low发现了HBS聚合 氧(O2)是HbAS对恶性疟原虫抗性的主要驱动因素。这应该表明是纯合子的HbSS 对疟疾具有更强的抵抗力，但矛盾的是，被感染的SCD患者(Hbss)却增加了 疟疾发病率和死亡率7-9。我提出了一种新的SCD和疟疾相互作用的假设模型 哪种RBC因子，如胎儿血红蛋白(HBF)，会在几乎没有HBS的情况下产生RBC储存库 如果发生聚合，可能会导致严重的疟疾。使用各种SCD RBC细胞类型，我将映射和 恶性疟原虫在SCD红细胞中的体外生长动力学模型及其影响因素 疟疾在这一人群中的传染性。这项工作为阐明分子机制奠定了基础。 是SCD和疟疾之间相互作用的基础，是确定新治疗方法的重要第一步 严重疟疾、SCD及其共病的目标。 我是一名儿科血液学家，由Manoj Duraisingh医生和Caroline Buckee医生共同指导，两人都是 哈佛大学陈天赫公共卫生学院。我的长期目标是成为一名独立的医生- 研究红细胞宿主对疟疾生长的影响并将这些因素作为治疗目标的科学家。 我以前的研究经验使我获得了进行体外研究的细胞生物学技能 疟疾的增长。通过关键导师K08奖，我现在已经做好了充分的准备，可以在 数学建模和寄生虫遗传学以更好地了解中国人血红蛋白病的流行病学 疟疾流行地区，评估在社区内引入红细胞多态的影响， 并为感染疟疾的SCD儿童寻找潜在的治疗目标。波士顿酒店 儿童医院和哈佛大学公共卫生学院是国际公认的研究 与多名专家研究人员在血红蛋白疾病、数学建模、 还有疟疾。波士顿儿童医院是我的主要机构，在培训青少年方面有着卓越的记录。 在儿科血液学研究中发挥领导作用的内科科学家。我已经组建了一支出色的 科学顾问委员会，由希金斯博士、戈德堡博士和桑卡兰博士组成。布鲁格纳拉博士和内森博士， 将继续担任我的职业导师，指导我的研究和培训经验。与 在本建议书中详细说明的结构化指导、教育和研究计划中，我将获得必要的 成为一名成功的独立调查者的专业知识，重点是血红蛋白疾病和疟疾。

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.