Dysregulation of the Human Ubiquitin Proteasome System in Pediatric Severe Malarial Anemia

项目总结 这项拟议的研究是一项为期四年的指导研究职业发展计划，旨在了解 人类泛素蛋白酶体系统调节失调的儿童(年龄，≤48个月)表现为 严重疟疾贫血(SMA；HB&lt；5.0g/dL)，在肯尼亚西部的一家农村转诊医院，一种完全流行的疾病 恶性疟疾流行地区。首席研究员Samuel Bonuke Anyona博士目前 肯尼亚马塞诺大学医学院医学生物化学讲师。这项建议 在最新研究的基础上，在新一代高级培训中添加了新的学习领域 转录学数据、复杂转录学和生化途径的分析以及治疗/药物 发现号。这些任务将通过道格拉斯·J博士进行的研究调查来实现。 美国新墨西哥大学的珀金斯(初级导师)实验室和马塞诺-UNM设施 肯尼亚的基苏木和锡亚。拟议的实验将使研究人员转向独立，因为 传染病科学家，重点研究UPS。此外，K43计划将为调查员配备 拥有新的技能，并促进与世界级科学家的合作。疟疾仍然是一个重要的全球健康问题 负担，全球报告的病例估计为2.19亿例(95%可信区间：2.03亿-2.62亿) 2017年。在肯尼亚西部，恶性疟原虫仍然是儿童发病率和 死亡，主要严重疾病表现为SMA。泛素-蛋白酶体系统(UPS)是 细胞内蛋白质降解和基本细胞过程调节的主要途径。两者都有 蛋白酶体和泛素与多种临床症状有关。在宿主-病原体相互作用期间， UPS对于抗原处理很重要，而恶性寄生虫具有修改宿主的能力 用于改善感染红细胞存活率的蛋白质组。然而，疟疾对主机UPS的影响仍然存在 未上报。我们最近对人类泛素化基因表达谱的研究表明，儿童 SMA在UPS中存在监管失调。在这些初步调查的基础上，进一步破译 人类UPS在儿童SMA发展中的作用，拟议的研究旨在：1)识别基因 在有助于SMA发展的宿主UPS中，2)确定SMA儿童是否发生了变化 由于UPS中的扰动而导致的蛋白质动态平衡(细胞压力)，以及3)识别能够改变 人类UPS可能成为未来治疗疟疾的疗法。

PROJECT SUMMARY The proposed study is a four-year mentored research career development program aimed at understanding dysregulation of the Human Ubiquitin Proteasome System (UPS) in children (age, ≤ 48 months) presenting with severe malaria anemia (SMA; Hb<5.0g/dL) at a rural County referral hospital in western Kenya, a holoendemic region for Plasmodium falciparum malaria. The Principal investigator, Samuel Bonuke Anyona, PhD is currently a Lecturer of Medical Biochemistry at the School of Medicine, Maseno University, Kenya. The proposal presented builds on recent research and adds new learning domains of advanced training in the generation of transcriptomic data, analysis of complex transcriptomic and biochemical pathways, and therapeutic/drug discovery. These tasks will be achieved through research investigations that will be conducted in Dr. Douglas J. Perkins (Primary Mentor) laboratories at the University of New Mexico, USA, and the Maseno-UNM facilities in Kisumu and Siaya, Kenya. The proposed experiments will transition the investigator towards independence as a scientist in infectious diseases, with a focus on the UPS. In addition, the K43 program will equip the investigator with new skill sets and foster collaboration with world-class scientists. Malaria remains a significant global health burden, with an estimated 219 million (95% confidence interval [CI]: 203–262 million) cases reported worldwide in 2017. In western Kenya, P. falciparum malaria remains one of the leading causes of childhood morbidity and mortality with the primary severe disease manifestation being SMA. The Ubiquitin-Proteasome System (UPS) is a major pathway for intracellular protein degradation and regulation of basic cellular processes. Both proteasomes and ubiquitin are associated with various clinical syndromes. During host-pathogen interactions, the UPS is important for antigen processing, and falciparum parasites have the ability to modify the host proteome for improved survival in infected erythrocytes. However, the impact of malaria on the host UPS remains unreported. Our recent investigations on human ubiquitylation gene expression profiles showed that children with SMA have dysregulation in the UPS. To build on these preliminary investigations, and to further decipher the role of the human UPS in the development of SMA in children, the proposed study aims to: 1) Identify genes in the host UPS that contribute to the development of SMA, 2) Determine if children with SMA have altered protein homeostasis (cellular stress) due to perturbations in the UPS, and 3) Identify compounds that modify the human UPS that could serve as future therapeutics for the treatment of malaria.