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:10225622
- 负责人:
- 金额:$ 6.98万
- 依托单位:
- 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:
- 关键词:AccountingAfricaAfricanAftercareAgeAnemiaArtemisininsBiochemical PathwayBiochemistryBiologicalBostonCareer ChoiceCase StudyCell physiologyCellsCellular StressCessation of lifeChildChildhoodClinicalClinical DataCollaborationsCommunicable DiseasesComplexConfidence IntervalsData AnalysesDevelopmentDiseaseDisease ProgressionDoctor of PhilosophyDrug TargetingEnrollmentEnzyme-Linked Immunosorbent AssayErythrocytesEukaryotaFDA approvedFalciparum MalariaFellowshipFosteringFutureGene ExpressionGene Expression ProfileGenerationsGenesGoalsHemoglobinHospital ReferralsHumanImmuneImmune responseInfrastructureInvestigationKenyaLaboratoriesLearningMalariaMalaria VaccinesMeasuresMediatingMedicalMentorsMonitorMorbidity - disease rateNatural ImmunityNew MexicoParasitesPathogenesisPathway interactionsPatternPharmaceutical PreparationsPlasmodiumPlasmodium falciparumPopulationPostdoctoral FellowPrincipal InvestigatorPrognosisProgram DevelopmentProkaryotic CellsProteomeRegulationResearchResearch PersonnelResistanceRisk AssessmentRoleSamplingScientistSignal PathwaySyndromeSystemTherapeuticTimeTrainingTraining ProgramsUbiquitinUniversitiesVisitantigen processingcareercareer developmentcell growth regulationcost effectivecytokinedrug discoveryexperimental studyglobal healthimprovedinternational centerlecturermalarial anemiamedical schoolsmortalitymulticatalytic endopeptidase complexnovelnovel therapeutic interventionpathogenperipheral bloodprogramsprotein degradationproteostasisrural countiesskillstranscriptomicstransmission processtreatment 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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Samuel Bonuke Anyona其他文献
Samuel Bonuke Anyona的其他文献
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{{ truncateString('Samuel Bonuke Anyona', 18)}}的其他基金
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 - 财政年份:2020
- 资助金额:
$ 6.98万 - 项目类别:
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:
10053741 - 财政年份:2020
- 资助金额:
$ 6.98万 - 项目类别:
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:
10460947 - 财政年份:2020
- 资助金额:
$ 6.98万 - 项目类别:
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