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

• 批准号: 10667473
• 负责人: Samuel Bonuke Anyona
• 金额: $ 7.1万
• 依托单位: MASENO UNIVERSITY
• 依托单位国家: 美国
• 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/10667473
• 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; Classification; Clinical; Clinical Data; Collaborations; Communicable Diseases; Complex; Confidence Intervals; Data; Development; Disease; Disease Progression; Doctor of Philosophy; Drug Targeting; Enrollment; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Eukaryota; FDA approved; Falciparum Malaria; Fellowship; Fogarty International Center; 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; Prognosis; 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; biomarker identification; career; career development; cell growth regulation; cost effective; cytokine; drug discovery; dynamic system; experimental study; global health; improved; lecturer; malarial anemia; medical schools; mortality; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; pathogen; peripheral blood; programs; protein degradation; proteostasis; rural counties; skills; transcriptomics; transmission process

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.

项目概要 拟议的研究是一项为期四年的指导性研究职业发展计划，旨在了解 儿童（年龄≤ 48 个月）的人类泛素蛋白酶体系统 (UPS) 失调 肯尼亚西部乡村县转诊医院出现严重疟疾贫血（SMA；Hb<5.0g/dL），这是一种霍乱流行 恶性疟原虫疟疾的首席研究员 Samuel Bonuke Anyona 博士目前正在研究该地区。 肯尼亚马塞诺大学医学院医学生物化学讲师。 提出的建立在最近的研究的基础上，并在生成中添加了高级培训的新学习领域 转录组数据、复杂转录组和生化途径的分析以及治疗/药物 这些任务将通过 Douglas J. 博士进行的研究调查来实现。 美国新墨西哥大学的 Perkins（主要导师）实验室和位于美国的 Maseno-UNM 设施 肯尼亚基苏木和西亚亚 拟议的实验将使研究者走向独立。 传染病科学家，重点研究 UPS 此外，K43 计划将为研究者提供装备。 掌握新的技能并促进与世界一流科学家的合作，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（95% 置信区间 [CI]：203-2.62 亿） 2017 年。在肯尼亚西部，恶性疟原虫疟疾仍然是儿童发病和死亡的主要原因之一。 泛素蛋白酶体系统（UPS）是主要严重疾病表现的死亡率。 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-病原体相互作用期间的各种临床综合征有关。 UPS 对于抗原加工很重要，恶性疟原虫具有改变宿主的能力 然而，疟疾对宿主 UPS 的影响仍然存在。 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 中存在失调现象 在这些初步调查的基础上，进一步破译。 为了了解人类 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 发展的主机 UPS 中，2) 确定患有 SMA 的儿童是否发生了改变 由于 UPS 扰动导致的蛋白质稳态（细胞应激），以及 3) 识别修饰蛋白质稳态的化合物 人类 UPS 可以作为未来治疗疟疾的疗法。

项目成果

Complement component 3 mutations alter the longitudinal risk of pediatric malaria and severe malarial anemia.

补体成分 3 突变改变了儿童疟疾和严重疟疾贫血的纵向风险。

• DOI: 10.1177/15353702211056272
• 发表时间: 2022
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Raballah,Evans;Anyona,SamuelB;Cheng,Qiuying;Munde,EllyO;Hurwitz,Ivy-Foo;Onyango,Clinton;Ndege,Caroline;Hengartner,NicolasW;Pacheco,MariaAndreína;Escalante,AnaniasA;Lambert,ChristopheG;Ouma,Collins;Obama,HenriCJrT;Schneid
• 通讯作者: Schneid

A Comprehensive COVID-19 Daily News and Medical Literature Briefing to Inform Health Care and Policy in New Mexico: Implementation Study.

• DOI: 10.2196/23845
• 发表时间: 2022-02-23
• 期刊: JMIR medical education
• 影响因子: 3.6
• 作者: Jarratt L;Situ J;King RD;Montanez Ramos E;Groves H;Ormesher R;Cossé M;Raboff A;Mahajan A;Thompson J;Ko RF;Paltrow-Krulwich S;Price A;Hurwitz AM;CampBell T;Epler LT;Nguyen F;Wolinsky E;Edwards-Fligner M;Lobo J;Rivera D;Langsjoen J;Sloane L;Hendrix I;Munde EO;Onyango CO;Olewe PK;Anyona SB;Yingling AV;Lauve NR;Kumar P;Stoicu S;Nestsiarovich A;Bologa CG;Oprea TI;Tollestrup K;Myers OB;Anixter M;Perkins DJ;Lambert CG
• 通讯作者: Lambert CG

Hemoglobinopathies, merozoite surface protein-2 gene polymorphisms, and acquisition of Epstein Barr virus among infants in Western Kenya.

• DOI: 10.1186/s12885-023-11063-2
• 发表时间: 2023-06-20
• 期刊: BMC CANCER
• 影响因子: 3.8
• 作者: Olewe, Perez K.;Awandu, Shehu Shagari;Munde, Elly O.;Anyona, Samuel B.;Raballah, Evans;Amolo, Asito S.;Ogola, Sidney;Ndenga, Erick;Onyango, Clinton O.;Rochford, Rosemary;Perkins, Douglas J.;Ouma, Collins
• 通讯作者: Ouma, Collins

Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya.

• DOI: 10.1186/s41182-022-00432-5
• 发表时间: 2022-06-25
• 期刊: Tropical medicine and health
• 影响因子: 4.5

Differential Gene Expression in Host Ubiquitination Processes in Childhood Malarial Anemia.

• DOI: 10.3389/fgene.2021.764759
• 发表时间: 2021
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Anyona SB;Raballah E;Cheng Q;Hurwitz I;Ndege C;Munde E;Otieno W;Seidenberg PD;Schneider KA;Lambert CG;McMahon BH;Ouma C;Perkins DJ
• 通讯作者: Perkins DJ