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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：
10436233
负责人：
Sayo Erick McCowin
金额：
$ 5.18万
依托单位：
UNIVERSITY OF VIRGINIA
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：
https://reporter.nih.gov/project-details/10436233
关键词：
5 year old Actins Agonist Alleles Bangladesh Biological Biological Assay Biopsy CRISPR/Cas technology Cause of Death Cell physiology Cells Child Child Development Child Health Child Mortality Childhood Chromosome Positioning Clinical Collection Colon Color Contracts Cryptosporidiosis Cytoskeleton Data Databases Development Diarrhea Disease Dominant-Negative Mutation Epithelial Epithelial Cells Genetic Genetic Polymorphism Genome Genotype Genotype-Tissue Expression Project Goals Human Human Genome Image Immunity Immunocompetent Immunocompromised Host Immunoglobulin A In Vitro Incidence Infant Infection Intestines Investigation Life Link Linkage Disequilibrium Malnutrition Manuscripts Measures Mediating Messenger RNA Molecular Monitor Mus Neurocognitive Outcome PRKCA gene Parasites Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Placebos Population Predisposition Preparation Protein Conformation Quantitative Trait Loci Regulation Research Proposals Risk Role Rotavirus Severities Severity of illness Single Nucleotide Polymorphism Small Intestines Symptoms Testing Therapeutic Time Tissues Transcript Variant Work alpha Actin base burden of illness cohort cytokine diarrheal disease effective therapy enteric infection experience genome wide association study genome-wide global health human pathogen in vivo inhibitor insight intestinal epithelium link protein mortality nitazoxanide parasite invasion pathogen protein function risk variant tool transcriptome 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.

项目总结