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Glucose Sensing and Hexokinases in the African Trypanosome

非洲锥虫中的葡萄糖传感和己糖激酶

基本信息

批准号：
9900822
负责人：
JAMES Culvin MORRIS
金额：
$ 22.11万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2022-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900822
关键词：
Africa South of the Sahara African African Trypanosomiasis Area Biochemical Biology Blood Circulation Cell physiology Cellular biology Centers of Research Excellence Collaborations Complex Core Facility Cues Data Detergents Development Disease Distant Ectopic Expression Environment Enzymes Funding Generations Genetic Glucose Glycolysis Glycosome Goals Hexokinase 2 Human Immunochemistry Infrastructure Insecta Laboratories Life Cycle Stages Light Mammals Measures Mediating Mentors Mentorship Metabolism Microscopy Mission Mitochondria Molecular Nutrient Organelles Outcome Parasites Pathway interactions Process Proteins Public Health Publications Regulation Research Research Personnel Resolution Risk Role Testing Trypanosoma Trypanosoma brucei brucei Tsetse Flies United States National Institutes of Health Universities Voltage-Dependent Anion Channel Work base enzyme activity glucose metabolism hexokinase imaging facilities infection risk innovation interest kinetosome matriculation neglected tropical diseases new therapeutic target pathogen peroxisome programs response therapeutic development unpublished works

项目摘要

PROJECT SUMMARY/ABSTRACT The infectious lifecycle stage of the African trypanosome, Trypanosoma brucei, relies exclusively on glycolysis for ATP generation. The parasite responds to dynamic environmental cues to regulate this pathway. The goal of this application is to resolve the mechanisms that regulate localization of the essential glycolytic enzymes, T. brucei hexokinase 1 and 2, with a particular emphasis on understanding the glucose-sensitive subcellular localization of the proteins. We have previously demonstrated that T. brucei hexokinase 2, which was heretofore believed to be limited in its distribution to a peroxisome-like organelle called the glycosome, has in addition a life-cycle dependent extra-glycosomal localization. In the bloodstream form parasites, the protein was found in the flagellum while in the insect stage the protein was found proximal to the basal bodies. Our preliminary data suggests that the localization is dependent on environmental glucose availability and that the hexokinases are associated with a detergent-insoluble fraction of the mitochondria. Using both ectopic expression of tagged proteins and immunochemistry in collaboration with microscopy and biochemical approaches, we will identify the enzyme domains that are required for localization. Additionally, we will begin to resolve the mechanisms required for glucose-dependent localization, with a particular focus on the association of the hexokinases with the parasite mitochondrion. Through these studies, new ways of targeting glucose metabolism, an essential parasite pathway, will be identified.

项目总结/文摘