Glycosome biogenesis in African trypanosomes

非洲锥虫中的糖体生物发生

• 批准号: 8813284
• 负责人: MEREDITH T MORRIS
• 金额: $ 24.7万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8813284
• 关键词: Affect; African; African Trypanosomiasis; Autophagocytosis; Behavior; Binding; Biogenesis; Biological; Biology; Blood Circulation; Cells; Centers of Research Excellence; Chagas Disease; Cutaneous Leishmaniasis; Data; Development; Dimerization; Disease; Drug Design; Drug Targeting; Endoplasmic Reticulum; Environment; Epitopes; Eukaryota; Exhibits; Funding; Future; Genes; Genome; Genomics; Glucose; Glycosome; Goals; Growth; Homologous Gene; Human Resources; In Vitro; Institutes; Knowledge; Laboratories; Leishmania; Lipids; Maintenance; Mammalian Cell; Mass Spectrum Analysis; Measures; Membrane; Membrane Proteins; Mentors; Mission; Modeling; Molecular; Mucocutaneous leishmaniasis; Nutrient; Organelles; Organism; Parasites; Pathway interactions; Peroxisome Proliferation; Phosphorylation; Population; Post-Translational Protein Processing; Process; Proliferating; Protein Analysis; Protein Import; Proteins; Proteome; Public Health; Recombinants; Research; Research Infrastructure; Research Personnel; Structure; System; Therapeutic; Tissues; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; Universities; Vesicle; Visceral Leishmaniasis; Work; Yeasts; abstracting; base; design; differential expression; drug development; environmental change; extracellular; fly; human disease; inhibitor/antagonist; innovation; insight; neglect; new therapeutic target; pathogen; peroxisome; protein expression; response; time use; transcriptome; transcriptome sequencing; vector; wortmannin

PROJECT SUMMARY/ABSTRACT Glycosomes are essential, parasite-specific organelles found in kinetoplastids, the causative agents of diseases affecting more than 70 million people globally. Currently, there is a fundamental gap in the knowledge of the mechanisms that regulate glycosome biology. The long-term goal is to identify the mechanisms involved in the maintenance, biogenesis and remodeling of glycosomes in the kinetoplastid Trypanosoma brucei. The central hypothesis is that glycosomes form de novo through the formation of pre- glycosomal vesicles that mature through a sequential process of protein import and predict that glycosome protein content changes during the maturation process and in response to environmental conditions. The short-term goal of this proposal is to characterize the molecular mechanisms that affect glycosome maturation and remodeling. The rationale for this project is that understanding the mechanisms that regulate glycosome biology will reveal attractive new drug targets. In pursuit of these goals, we will carry out the following specific aims: 1) Identify the post-translational modifications of the glycosome protein, TbPEX11, in different glycosome populations, 2) Identify the pathways that regulate glycosome remodeling in response to changes in environmental conditions 3) Identify glucose-dependent changes in glycosome protein expression and transcriptome response to extracellular glucose. This work is significant and will positively impact the field, as it will resolve mechanisms of glycosome biogenesis and elucidate processes that can be exploited for therapeutic design.

项目总结/摘要 糖体是在动质体中发现的必需的寄生虫特异性细胞器， 全球有超过7000万人感染疾病。目前，在这方面存在着根本性的差距。 了解调节糖体生物学的机制。长期目标是确定 参与动质体中糖体的维持、生物发生和重塑的机制 布氏锥虫核心假设是糖体通过形成前- 糖体囊泡通过蛋白质输入的顺序过程成熟，并预测糖体 蛋白质含量在成熟过程中和响应于环境条件而变化。的 这项建议的短期目标是描述影响糖体成熟的分子机制 和重塑。这个项目的基本原理是，了解调节糖体的机制， 生物学将揭示有吸引力的新药物靶点。为了实现这些目标，我们将开展以下具体工作： 目的：1）鉴定糖体蛋白TbPEX 11在不同糖体中的翻译后修饰 2）确定响应于细胞内糖体的变化而调节糖体重塑的途径， 3）鉴定糖体蛋白表达的葡萄糖依赖性变化， 转录组对细胞外葡萄糖的应答。这项工作意义重大，将对该领域产生积极影响， 它将解决糖体生物发生的机制，并阐明可用于 治疗设计