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

项目摘要 这项拟议中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 儿童（年龄≤ 48个月）的人泛素蛋白酶体系统（UPS）失调， 严重疟疾贫血（SMA; Hb<5.0g/dL）在肯尼亚西部的一家乡村县转诊医院， 恶性疟原虫疟疾地区。首席研究员Samuel Bonuke Anyona博士目前 肯尼亚Maseno大学医学院医学生物化学讲师。该提案 提出了建立在最近的研究，并增加了新的学习领域的高级培训，在一代 转录组学数据、复杂转录组学和生物化学途径的分析以及治疗/药物 的发现这些任务将通过道格拉斯J博士进行的研究调查来实现。 美国新墨西哥州大学的Perkins（初级导师）实验室和 肯尼亚的基苏穆和锡亚亚。拟议的实验将使研究人员向独立过渡， 他是传染病方面的科学家，主要研究UPS。此外，K43计划将使调查人员 新的技能组合，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，估计全球报告了2.19亿（95%置信区间[CI]：2.03 - 2.62亿）例病例 2017年在肯尼亚西部，恶性疟原虫疟疾仍然是儿童发病的主要原因之一， 主要重度疾病表现为SMA的死亡率。泛素-蛋白酶体系统（UPS） 是细胞内蛋白质降解和调节基本细胞过程的主要途径。两 蛋白酶体和泛素与各种临床综合征有关。在宿主-病原体相互作用期间， UPS对于抗原加工是重要的，并且恶性疟原虫具有修饰宿主的能力 蛋白质组用于提高感染红细胞的存活率。然而，疟疾对东道国UPS的影响仍然存在， 未报告。我们最近对人类泛素化基因表达谱的研究表明， SMA患者的UPS有失调。在这些初步调查的基础上， 人类UPS在儿童SMA发展中的作用，拟议的研究旨在：1）确定基因 2）确定SMA儿童是否改变了 由于UPS中的扰动，蛋白质稳态（细胞应激），和3）鉴定修饰 人类UPS可以作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.