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Identification and characterization of early encystation genes in the human parasite Entamoeba histolytica

人类寄生虫溶组织内阿米巴早期成囊基因的鉴定和表征

基本信息

批准号：
10647086
负责人：
CHERYL Jean INGRAM-SMITH
金额：
$ 22.42万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647086
关键词：
Acetate-CoA Ligase Acetates Amebic Liver Abscess Amebic colitis Back Bioinformatics Candidate Disease Gene Carrier State Cell Density Cell Wall Cells Cessation of life Chitin Coenzyme A Cues Cyst Data Developing Countries Disease Distant Entamoeba histolytica Entamoeba invadens Environment Expression Library Food Contamination Foundations Gene Expression Profiling Gene Library Gene Silencing Genes Genetic Glucose Goals Growth Heat Stress Disorders Human In Vitro Infection Ingestion Investigation Knowledge Laboratories Laboratory culture Large Intestine Libraries Mediating Methods Mission Oxidative Stress Parasites Persons Physiological Play Process Propionates Protocols documentation Public Health Regulation Regulator Genes Reproducibility Reptiles Research Role Sampling Scientist Signal Pathway Signal Transduction Small Intestines Stimulus Stress System Technology Time Translating United States National Institutes of Health Volatile Fatty Acids biological adaptation to stress candidate identification cell motility contaminated water deprivation excystation human pathogen interest nitrosative stress overexpression pathogen prevent programs response screening thioester transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY The inability of Entamoeba histolytica to form infectious cysts in the laboratory setting has greatly hindered investigation of this crucial stage in the infection and disease cycle of this human pathogen that causes amoebic dysentery in ~100 million people each year worldwide. Instead, scientists have been forced to rely on studies with the distantly related reptile pathogen Entamoeba invadens. The long-term goal of our research program is to determine how E. histolytica adapts to different environments it encounters during infection and the disease process. In particular, we are interested in how E. histolytica adapts to the environment of the large intestine in order to colonize there and spread disease by formation and dissemination of infectious cysts. We have now established a reproducible system for encystation and excystation of E. histolytica in culture. This major technological advance enables us to pursue an understanding of how E. histolytica senses and responds to environmental cues that signal conversion from motile trophozoite to infectious cyst and back. As part of our long-term goal, the overall objective of this proposal is to identify and characterize genes responsible for initiation of encystation. The rationale for the proposed project is that understanding how E. histolytica senses and responds to its environment through encystation will lead to a better understanding of how this pathogen can survive and thrive as it encounters very diverse environments during different stages of its infectious cycle. We will pursue two specific aims: (1) identify encystation initiation genes using RNAseq; and (2) screen an overexpression library for genes involved in initiation of encystation in E. histolytica. Candidate genes identified through these two approaches will be validated through analysis of gene silenced and gene overexpression strains. We will evaluate these strains for their ability to encyst, excyst, and establish standard trophozoite growth as well as their responses to other stresses such as heat, oxidative, and nitrosative stress to determine whether any of the candidate genes play a general stress response role. As part of the proposed research, we will optimize our encystation protocol and determine other environmental signals that trigger more rapid encystation. The complementary RNAseq and library screening approaches should allow us to identify genes required for the earliest stages of encystation prior to chitin cell wall formation as well as regulatory genes. The significance of this research is that we can now begin to understand the interplay of environmental signals that regulate encystation and how these signals are acted upon by E. histolytica. This research will have an important impact on the field in that for the first time the processes involved in stage conversion can be fully studied directly in the human pathogen to provide a better understanding of how E. histolytica can thrive during colonization and continue to propagate disease through spread of infectious cysts.

项目总结