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Regulation of calcium signaling in the human malaria parasite

人类疟疾寄生虫中钙信号传导的调节

基本信息

批准号：
9759759
负责人：
Silvia N Moreno
金额：
$ 18.88万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759759
关键词：
Affect Animal Model Antimalarials Area Back Binding Binding Proteins Biochemical Biological Biological Assay Biological Process Biology Biotin Buffers CRISPR/Cas technology Calcium Calcium Signaling Calcium ion Calnexin Cells Cessation of life Clinic Clinical Cytoplasm Cytosol Data Defect Disease Drug Targeting Drug resistance Drug usage Endoplasmic Reticulum Erythrocytes Genes Genetic Genome Goals Growth Homeostasis Human Infection Inositol Ions Knock-out Label Life Cycle Stages Ligase Malaria Malaria Vaccines Molecular Organelles Organism Parasites Pathway interactions Plasmodium Plasmodium falciparum Population Proteins Regulation Research Resistance Resistance development Role Ryanodine Receptor Calcium Release Channel Sexual Development Signal Pathway Signal Transduction System Transmembrane Domain asexual base conditional mutant drug development experimental study falls gene therapy human disease knock-down loss of function mortality mutant new therapeutic target novel obligate intracellular parasite parasite invasion receptor resistant strain response uptake

项目摘要

Project Summary The deadliest form of human malaria is caused by the eukaryotic parasite Plasmodium falciparum, which is responsible for nearly 450,000 deaths every year. Nearly half of the world’s population lives in areas where malaria is endemic, resulting in almost ~250 million infections each year. As yet, there are no effective vaccines against malaria and antimalarial drugs are the mainstay of treatment. Unfortunately, the parasite has gained resistance to all antimalarial drugs used in the clinic and these drug-resistant strains are spreading throughout the world. Thus, it is crucial that we constantly identify potential novel drug targets to stay ahead of this deadly disease. Understanding the signaling pathways that drive the biology of the parasite will provide new antimalarial drug targets that are unique to the parasite and absent in the host. Calcium ion (Ca2+) signaling has emerged as one of the major drivers of the life cycle of P. falciparum. The goal of this proposal is to study Ca2+ signaling and the pathways that regulate ion fluctuations in malaria parasites. In P. falciparum, similar to other eukaryotic organisms, the cytoplasmic levels of Ca2+ is very low and its concentration rises in the cytoplasm in response to specific signals. This increased cytosolic Ca2+ results in a signaling cascade that that is essential for the life cycle of the parasite. Once the signal subsides, the levels of cytosolic Ca2+ falls back via uptake into intracellular Ca2+ stores, such as the endoplasmic reticulum. The P. falciparum genome lacks several canonical genes that are known to be essential for Ca2+ signaling in other well- studied eukaryotic organisms. Therefore, we will target the only soluble protein with Ca2+ binding domains that localizes to the major intracellular Ca2+ store, the endoplasmic reticulum. We hypothesize that this protein regulates the release and uptake of Ca2+ from this organelle. Our preliminary data show that this gene is essential for the asexual life cycle of the parasite and is required for the invasion of the parasite into its host red blood cell. We will utilize genetic, cellular, and biochemical approaches to define the role of this gene in regulating Ca2+ signaling and the invasion of P. falciparum into the host cell. These include the use of genetically encoded Ca2+ indicators to reveal the fluctuations of Ca2+ during the intraerythrocytic life cycle of P. falciparum as well as the effect of genetic interventions on the homeostasis of Ca2+. A second independent proximity-based labeling approach will be undertaken to isolate and discover novel partners of the targeted gene to define the network of genes required to regulate the flow of Ca2+ within the P. falciparum infected human red blood cells. Achieving the aims of this study will reveal the essential parasite-specific pathways that regulate Ca2+ signaling, which can be targeted for antimalarial drug development.

项目总结