Polymorphisms link Protein Kinase C-α to Cryptosporidia susceptibility in 1st year of life
多态性将蛋白激酶 C-α 与生命第一年的隐孢子虫易感性联系起来
基本信息
- 批准号:9910673
- 负责人:
- 金额:$ 3.41万
- 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:2020-07-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:5 year oldActinsAgonistAllelesBangladeshBiologicalBiological AssayBiopsyCRISPR/Cas technologyCause of DeathCell physiologyCellsChildChild DevelopmentChild HealthChild MortalityChildhoodChromosome PositioningClinicalCollectionColonColorContractsCryptosporidiosisCytoskeletonDataDatabasesDevelopmentDiarrheaDiseaseDominant-Negative MutationEpithelialEpithelial CellsEpitheliumGeneticGenetic PolymorphismGenomeGenotypeGenotype-Tissue Expression ProjectGoalsHumanHuman GenomeImageImmunityImmunocompetentImmunocompromised HostImmunoglobulin AIn VitroIncidenceInfantInfectionIntestinesInvestigationLifeLinkLinkage DisequilibriumMalnutritionManuscriptsMeasuresMediatingMessenger RNAMolecularMonitorMusNeurocognitiveOutcomePRKCA geneParasitesPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhenotypePhosphotransferasesPlacebosPopulationPredispositionPreparationProtein ConformationQuantitative Trait LociRegulationResearch ProposalsRiskRoleRotavirusSeveritiesSeverity of illnessSingle Nucleotide PolymorphismSmall IntestinesSymptomsTestingTherapeuticTimeTissuesTranscriptVariantWorkalpha Actinbaseburden of illnesscohortcytokinediarrheal diseaseeffective therapyenteric infectionexperiencegenome wide association studygenome-wideglobal healthhuman pathogenin vivoinhibitor/antagonistinsightintestinal epitheliumlink proteinmortalitynitazoxanideparasite invasionpathogenprotein functionrisk varianttooltranscriptome sequencing
项目摘要
PROJECT SUMMARY
Cryptosporidia is a diarrheal pathogen with an important impact on global health. Overall, diarrheal disease is
estimated to be responsible for 10% of under 5-year old child mortality, and the recent Global Burden of
Diseases analysis of diarrheal mortality found that Cryptosporidia was second only to rotavirus as a cause of
death in children under five years old (5). Nitazoxanide, currently the only approved drug for Cryptosporidia
infection, is only moderately effective for treatment of immunocompetent patients. Furthermore, it is only
equivalent to placebo in severely immunocompromised patients. Clinical presentation of Cryptosporidia
infection is variable in severity; some patients experience severe diarrheal illness while some infections remain
subclinical. Although the cause for the wide spectrum of disease is poorly understood, several studies have
demonstrated long-term clinical implications of both asymptomatic and symptomatic infection. We performed a
genome-wide association study (GWAS) on infants in Bangladesh within the first year of life. We evaluated the
association between 6.5 million single nucleotide polymorphisms (SNPs) across the human genome and
symptomatic Cryptosporidia infection in three independent patient cohorts. This analysis revealed a highly
significant statistical association of multiple SNPs in the PRKCA gene and susceptibility to Cryptosporidia
diarrhea. Each copy of the risk allele increased the risk of contracting cryptosporidiosis by 2.4 times in the first
year of life. The most significant SNP in PRKCA is an eQTL in the GTex database, however, a definitive link
between PKCα and Cryptosporidia has not yet been established. The PKCα kinase is a primary regulator of
actin and during intracellular invasion, Cryptosporidia induces host cell actin remodeling. Further investigation
into how the PRKCA gene variation relates to PKCα function and susceptibility to Cryptosporidia infection will
provide insight into the pathogenesis of an important human pathogen to cause disease. We hypothesize that
host PKCα is required for Cryptosporidia invasion of intestinal epithelium through remodeling of actin
cytoskeleton. Based on this preliminary data, we aim to characterize (i) the role of PKCα in Cryptosporidia
invasion of the intestinal epithelium in vitro and in vivo (ii) define the impact of the SNPs on PRKCA expression
and downstream function, and (iii) identify if PRKCA expression mediates severity of disease in children. To
accomplish this, the research proposal includes active investigation of Cryptosporidia both in the field and at
the bench. Here, we propose bridging two approaches for scientific discovery by using molecular tools to
examine PRKCA and monitoring clinical outcomes in genotyped human children. The overarching goal of
these independent yet interacting aims will be the translational development of host PKCα as a potential
target to advance critically needed treatments for cryptosporidiosis.
项目概要
隐孢子虫是一种腹泻病原菌,对全球健康具有重要影响。总体来说,腹泻病是
据估计,儿童死亡率占 5 岁以下儿童死亡率的 10%,而最近的全球负担
腹泻死亡率的疾病分析发现,隐孢子虫是仅次于轮状病毒的第二大腹泻病死因。
五岁以下儿童死亡 (5)。硝唑尼特,目前唯一批准治疗隐孢子虫的药物
感染,对于免疫功能正常的患者的治疗仅具有中等效果。此外,它只是
相当于严重免疫功能低下患者的安慰剂。隐孢子虫的临床表现
感染的严重程度各不相同;一些患者出现严重腹泻病,而一些感染仍然存在
亚临床的。尽管对广泛疾病的原因知之甚少,但一些研究表明
证明了无症状和有症状感染的长期临床影响。我们执行了一个
对孟加拉国一岁以内婴儿进行的全基因组关联研究(GWAS)。我们评估了
人类基因组中 650 万个单核苷酸多态性 (SNP) 之间的关联
三个独立患者队列中有症状的隐孢子虫感染。这项分析揭示了一个高度
PRKCA 基因中多个 SNP 与隐孢子虫易感性的显着统计学关联
腹泻。每个风险等位基因拷贝在第一个拷贝中都会使感染隐孢子虫病的风险增加 2.4 倍
生命的一年。 PRKCA 中最重要的 SNP 是 GTex 数据库中的 eQTL,但是,一个明确的链接
PKCα 和隐孢子虫之间的关系尚未确定。 PKCα 激酶是主要调节因子
肌动蛋白和细胞内侵袭过程中,隐孢子虫诱导宿主细胞肌动蛋白重塑。进一步调查
研究 PRKCA 基因变异如何与 PKCα 功能和对隐孢子虫感染的易感性相关
提供对引起疾病的重要人类病原体的发病机制的深入了解。我们假设
隐孢子虫通过肌动蛋白重塑入侵肠上皮需要宿主 PKCα
细胞骨架。基于这些初步数据,我们的目标是描述 (i) PKCα 在隐孢子虫中的作用
体外和体内肠上皮的侵袭 (ii) 确定 SNP 对 PRKCA 表达的影响
和下游功能,(iii) 确定 PRKCA 表达是否介导儿童疾病的严重程度。到
为了实现这一目标,该研究计划包括在现场和现场对隐孢子虫进行积极调查
板凳。在这里,我们建议通过使用分子工具来桥接两种科学发现方法
检查 PRKCA 并监测基因分型人类儿童的临床结果。总体目标是
这些独立但相互作用的目标将是将宿主 PKCα 转化为潜在的
目标是推进急需的隐孢子虫病治疗方法。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Sayo Erick McCowin其他文献
Sayo Erick McCowin的其他文献
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{{ truncateString('Sayo Erick McCowin', 18)}}的其他基金
Polymorphisms link Protein Kinase C-α to Cryptosporidia susceptibility in 1st year of life
多态性将蛋白激酶 C-α 与生命第一年的隐孢子虫易感性联系起来
- 批准号:
10180871 - 财政年份:2020
- 资助金额:
$ 3.41万 - 项目类别:
Polymorphisms link Protein Kinase C-α to Cryptosporidia susceptibility in 1st year of life
多态性将蛋白激酶 C-α 与生命第一年的隐孢子虫易感性联系起来
- 批准号:
10436233 - 财政年份:2020
- 资助金额:
$ 3.41万 - 项目类别:
Polymorphisms link Protein Kinase C-α to Cryptosporidia susceptibility in 1st year of life
多态性将蛋白激酶 C-α 与生命第一年的隐孢子虫易感性联系起来
- 批准号:
10649620 - 财政年份:2020
- 资助金额:
$ 3.41万 - 项目类别:
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