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

儿童严重疟疾贫血中人泛素蛋白酶体系统的失调

基本信息

批准号：
10053741
负责人：
Samuel Bonuke Anyona
金额：
$ 6.9万
依托单位：
MASENO UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053741
关键词：
Accounting Africa African Aftercare Age Anemia Artemisinins Biochemical Pathway Biochemistry Biological Boston Career Choice Case Study Cell physiology Cells Cellular Stress Cessation of life Child Childhood Clinical Clinical Data Collaborations Communicable Diseases Complex Confidence Intervals Data Analyses Development Disease Disease Progression Doctor of Philosophy Drug Targeting Enrollment Enzyme-Linked Immunosorbent Assay Erythrocytes Eukaryota Expression Profiling FDA approved Falciparum Malaria Fellowship Fostering Future Gene Expression Gene Expression Profile Generations Genes Goals Hemoglobin Hospital Referrals Human Immune Immune response Infrastructure Investigation Kenya Laboratories Learning Malaria Malaria Vaccines Measures Mediating Medical Mentors Monitor Morbidity - disease rate Natural Immunity New Mexico Parasites Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Plasmodium Plasmodium falciparum Population Postdoctoral Fellow Principal Investigator Program Development Prokaryotic Cells Proteome Regulation Research Research Personnel Resistance Risk Assessment Role Sampling Scientist Signal Pathway Syndrome System Therapeutic Time Training Training Programs Ubiquitin Universities Visit antigen processing career career development cell growth regulation cost effective cytokine drug discovery experimental study global health improved international center lecturer malarial anemia medical schools mortality multicatalytic endopeptidase complex novel novel therapeutic intervention outcome forecast pathogen peripheral blood programs protein degradation proteostasis rural counties skills transcriptomics transmission process treatment duration

项目摘要

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.

项目摘要支撑研究是一项为期四年的指导研究职业发展计划儿童（≤48个月）的人类泛素蛋白酶体系统（UPS）的失调在肯尼亚西部的一家农村县转诊医院，严重的疟疾贫血（SMA； HB <5.0g/dl）恶性疟疾疟疾疟疾地区。肯尼亚Maseno大学医学院的医学生物化学讲师介绍的建立在最近的研究基础上，并增加了对高级培训的新学习转录组数据，复杂转录组和生化途径的分析以及治疗/药物发现这些任务。新墨西哥大学的珀金斯（主要导师）实验室和Maseno-Unm设施肯尼亚的Kisumu和Siaya。传染病的科学家，重点是UPS。通过新的技能和与世界一流的科学家的合作。负担，估计有2.19亿（95％的信心国际[CI]：203-262万）Casses在全球范围内报道了世界 2017年。在肯尼亚西部，恶性疟原虫疟疾仍然是造成儿童时期病因的主要原因之一主要严重疾病表现的死亡率是SMA。细胞内蛋白质降解和基本细胞过程调节的主要途径。蛋白酶体和泛素与宿主 - 病原体相互作用的各种临床综合症有关 UPS是重要的临时，恶性疟原虫必须修改主机蛋白质组可改善感染红细胞的生存率。未报告我们最近对人类无处不在的投资 SMA在UPS中有失调。人类UPS在儿童SMA发展中的作用在有助于SMA发展的主机中，2）确定SMA儿童是否发生了变化蛋白质稳态（细胞应激）由于UPS的扰动而引起的，3）识别改变您的成分可以作为疟疾治疗的未来治疗学的人类UPS。