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Elucidating the Mechanistic Basis for Phagotrophy in the Protozoan Trypansoma cruzi

阐明原生动物克氏锥虫吞噬作用的机制基础

基本信息

批准号：
10630908
负责人：
RONALD DREW ETHERIDGE
金额：
$ 30.2万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630908
关键词：
Actin-Binding Protein Actins Active Biological Transport Amino Acids Area Binding Binding Proteins Biogenesis Biology Carbon Cell Survival Cell membrane Cells Cholesterol Cilia Complement Complex Consumption Curiosities Cytoplasm Digestion Dimensions Eating Ecosystem Endocytosis Environment Eukaryota Family Filament Flagella Food Food Webs Goals Health Human In Vitro Integral Membrane Protein Knock-out Life Light Lysosomes Mass Spectrum Analysis Mastigophora Mechanics Mediating Membrane Microdomains Methodology Methods Molecular Molecular Analysis Motor Myosin ATPase Nutrient Oral Organelles Organism Parasites Parasitic Diseases Phosphotransferases Photons Plants Play Polymers Positioning Attribute Predatory Behavior Process Protein Isoforms Proteins Protozoa Publishing Receptor Protein-Tyrosine Kinases Receptor Signaling Reporting Role Route Signal Pathway Signal Transduction Signaling Molecule Site-Directed Mutagenesis Source Structure Surface Techniques Trypanosoma cruzi Tubular formation Vesicle Work extracellular feeding glycosylation induced pluripotent stem cell inhibitor insight microbial model organism overexpression palmitoylation parasitism polymerization receptor recruit tool trafficking transmission process

项目摘要

PROJECT SUMMARY Whether its photons or fries eating is fundamental for life. From this basic principle, living organisms have evolved innumerable strategies to capture energy and nutrients from their environment, leading, in turn, to the incredible ecological diversity spanning the gamut from light eating photosynthetic autotrophs to predatory heterotrophs. As part of the world’s aquatic ecosystems, the expansive family of heterotrophic protozoan predators play a critical role in environmental carbon and nutrient cycling as they consume 75% of primary producing planktonic autotrophs daily. The vast majority of these flagellated phagotrophs use self-generated currents to funnel their prokaryotic prey into an ancient and highly enigmatic feeding apparatus prior to digestion. This feeding structure begins as a plasma membrane surface opening (cytostome), descends into an internal tubular invagination (cytopharynx) and ends with prey being enveloped within budding vesicles destined for lysosome fusion. Here we refer to this organelle as the cytostome/cytopharynx complex or SPC and, despite its near ubiquitous presence in protozoans, next to nothing is known mechanistically about how this structure is formed or functions. Intriguingly, a class of these phagotrophic predators known as the kinetoplastids, gave rise to a lineage of parasitic protozoa that can infect a wide variety of organisms ranging from plants to humans. Curiously, one species in particular, Trypanosoma cruzi, retained this ancestral organelle much like its free-living relatives (e.g. bodonids) and continues to use it as its primary route of endocytosis. Due to the fact that T. cruzi is easily culturable, genetically tractable and not reliant on SPC mediated endocytosis for viability in vitro, we have been able to conduct the first ever in-dept molecular analyses of this ubiquitous feeding organelle. Our initial published work on this structure described the first known proteins targeted to the SPC and was followed by a report on the identification of a family of SPC targeted myosin motors that we show contribute directly to the endocytic process. As a continuation of these studies, this proposal seeks to generate a holistic understanding of how SPC mediated endocytosis fundamentally functions. We will begin by dismantling the unified activity of endocytosis into its constituent processes; cargo capture through surface receptors (Aim1), receptor signal transduction and activation of endocytic machinery (Aim2) and finally active transport of phagocytosed cargo along the SPC for digestion (Aim3). Each of these aims will address important basic aspects of protozoan biology that continue to remain poorly understood. Critically, this proposal will combine both a broad approach to identify cytostomal surface receptors and SPC specific signaling components with a focused analysis of the role of the Act2 isoform in the endocytic process. By combining this model organism with a broad range of cutting-edge molecular tools and methodologies, we will be able to elucidate the mechanistic basis of this ancient protozoal feeding apparatus with the goal of providing insight into basic processes ranging from microbial food webs to parasitic diseases.

项目总结