权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Elucidating the Role of Endocytosis Via the Cytostome in the Life Cycle of Trypanosoma cruzi

阐明细胞口内吞作用在克氏锥虫生命周期中的作用

基本信息

批准号：
10626864
负责人：
RONALD DREW ETHERIDGE
金额：
$ 47.98万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626864
关键词：
Address Adult Americas Arthropod Vectors Basic Science Biological Biology CRISPR/Cas technology Cell membrane Cells Chagas Disease Clinical Complex Cytosol Data Defect Digestion Disease Elements Endocytosis Environment Etiology Family Feces Gastrointestinal tract structure Gene Deletion Genes Genetic Goals Growth Hindgut Human Individual Infection Ingestion Insect Vectors Insecta Invaded Knock-out Leishmania Life Life Cycle Stages Lipids Measurable Mediating Molecular Molecular Analysis Molecular Motors Molecular Target Motor Myosin ATPase Nutrient Oral Organelles Organism Orphan Parasites Parasitic infection Pathway interactions Persons Play Populations at Risk Process Proteins Proteomics Publishing Rectum Resources Role Structure Surface Techniques Technology Time Trypanosoma brucei brucei Trypanosoma cruzi Tubular formation Validation Vesicle Work burden of illness combat comparative electron tomography extracellular feeding insight knockout gene lipidomics mutant neglect novel obligate intracellular parasite pathogen protein complex rectal subcellular targeting tool transmission process uptake vector vector transmission virtual

项目摘要

PROJECT SUMMARY The etiological agent of Chagas disease, Trypanosoma cruzi, is an obligate intracellular parasite that infects an estimated 10 million people in the Americas, with an at-risk population of 70 million. Despite its recognition as the highest impact parasitic infection of the Americas, Chagas disease remains underreported, understudied and underfunded. Basic research into the biology of T. cruzi has previously been hindered by a lack of efficient genetic tools, but the advent of CRISPR/Cas9 gene editing technology has cleared the way for more in-depth molecular analyses. Among the human infecting parasitic trypanosomatids, T. cruzi is extremely unique for a number of reasons: it develops into its infectious form in the hindgut of insects, is transmitted to its mammalian host via the feces of its insect vector, lives directly in the cytosol of its mammalian host cell and utilizes an ancient feeding organelle to endocytose extracellular material in a manner much like its bacterivorous free- living relatives. This endocytic structure is composed of a long tubular invagination (cytopharynx) starting at a surface plasma membrane pore (cytostome) which we refer to here as the cytostome/cytopharynx complex or SPC. The SPC is a highly dynamic organelle that is present and functional only in the replicating forms of the parasite and disassembles during the transition to its infectious stages. Until recently the SPC had only been examined using electron tomography techniques and had resisted molecular analysis as the protein components comprising it remained elusive. Our initial published work described the first proteins known to be targeted to the SPC and was followed by the identification of a family of SPC targeted myosin motors that we show contribute directly to the endocytic process. Recently, however, we have identified an essential myosin regulatory component of the SPC (MyAP1), a knockout of which resulted in parasites that are completely devoid of measurable endocytosis and who are defective in their ability to scavenge host lipids. Although viable in culture, we have also demonstrated through infections of the insect vector (R. prolixus) that endocytosis is critical for the parasite to be able to establish a robust infection and colonize the insect hindgut, a necessary step for effective transmission to its mammalian host. Completion of this study will allow us to continue to elucidate the molecular machinery responsible for the formation and function of the SPC as well as give insight into why it is that T. cruzi retained this ancient mode of nutrient uptake. Our endocytic-null mutant also gives us the unique opportunity to finally examine the “endocytome” of this parasite. Although not limited to lipids, we are excited by preliminary data allowing us for the first time to now distinguish which lipids are actively being scavenged through endocytosis from those which the parasite is able to endogenously produce for itself. The goal for this proposal is ultimately to give greater insight into parasite pathways essential for vector transmission as well as provide a window into the biosynthetic pathways that are actively present and necessary for parasite viability.

项目总结