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

项目总结/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 新生儿每年1.在SCD中，突变的血红蛋白（HbS）聚合2并导致红细胞变成镰刀状- 形状。SCD仍然普遍存在，因为杂合子携带者（HbAS）对疟原虫具有部分抗性 恶性疟疾3，4，每年造成40万人死亡5。我最近发现，在低血糖中， 氧气（O2）作为HbAS对恶性疟原虫耐药性的主要驱动因素6。这应该提示纯合子HbSS 赋予了对疟疾更大的抵抗力，但矛盾的是，感染SCD的个体（HbSS） 疟疾发病率和死亡率7 -9.我提出了一个新的假设模型SCD和疟疾的相互作用， 这些红细胞因子，如胎儿血红蛋白（HbF），创造了一个红细胞储库，其中几乎没有HbS 聚合发生时，可能会导致严重的疟疾。使用各种SCD RBC细胞类型，我将绘制和 建立恶性疟原虫在SCD红细胞中的体外生长动力学模型，并鉴定影响 疟疾的传染性。这项工作是阐明分子机制的基础 这是SCD和疟疾之间相互作用的基础，也是确定新治疗方法的重要第一步。 严重疟疾、SCD及其合并症的目标。 我是一名儿科血液学家，由Manoj Duraisingh博士和Caroline Buckee博士共同指导， 哈佛的T. H.公共卫生学院。我的长期目标是成为一名独立的医生- 科学家研究红细胞宿主对疟疾生长的影响，并以这些因素为治疗目标。 我以前的研究经验使我获得了细胞生物学的技能，在体外研究 疟疾增长。通过关键的指导K 08奖，我现在处于有利地位，以获得新的技能， 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，评估在社区内引入RBC多态性的影响， 并为感染疟疾的SCD儿童找到潜在的治疗靶点。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 与血红蛋白病，数学建模， 和疟疾。波士顿儿童医院，我的主要机构，在培训年轻人方面有着杰出的记录。 儿科血液学研究中的领导角色。我召集了一个优秀的 科学顾问委员会，由希金斯博士，戈德堡，和Sankaran。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 结构化的指导，教育和研究计划，详细介绍了本建议书，我将获得必要的 专业知识，成为一个成功的独立调查员，专注于血红蛋白病和疟疾。

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.