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Elements of the Ca2+ signal transduction pathway of Toxoplasma gondii

弓形虫Ca2信号转导通路的元件

基本信息

批准号：
10154355
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：
2020
资助国家：
美国
起止时间：
2020-12-14 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154355
关键词：
Active Sites Address Adhesives Amino Acid Motifs Amino Acids Antiparasitic Agents Automobile Driving Bacterial Adhesins Binding Binding Proteins Biochemical Biological Biological Process Biotin CALM1 gene Calcium Calcium Binding Calcium Signaling Calcium ion Calcium-Binding Proteins Calmodulin Cell membrane Cell physiology Cells Clinical Complement Complex Dimerization Disease EF Hand Motifs EF-Hand Domain Elements Epitopes Eukaryota Eukaryotic Cell Event Future Goals Growth Individual Infection Invaded Ion Channel Ions Knowledge Label Ligase Lytic Phase Medical Molecular Molecular Conformation Mutation Organism PAWR protein Parasites Pathogenesis Pathology Pathway interactions Play Proteins Reporting Role Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Structure Toxoplasma gondii Toxoplasmosis Transducers Virulence Work cell motility chemotherapy extracellular insight knock-down novel obligate intracellular parasite pathogen protein protein interaction response sensor

项目摘要

Toxoplasma gondii is an obligate intracellular parasite that replicates inside host cells. T. gondii belongs to the Apicomplexan phylum which also includes a number of pathogens of medical and veterinary relevance. The clinical manifestations of these diseases are a direct result of the growth of parasites within host cells. Replication and dissemination within the host are essential mechanisms by which T. gondii causes disease. T. gondii engages in multiple rounds of a lytic cycle, which consists of attachment and secretion of unique adhesins, invasion of host cells, replication, egress and search of another host cell to invade. Almost all of these biological functions are triggered by an increase in cytosolic free calcium (Ca2+), followed by stimulation of signaling cascades that are poorly characterized. Many of the transducing elements downstream to Ca2+ are either not known or have not been characterized or their interaction with other elements in the signaling cascade is not clear. Discovery and characterization of new signaling elements is highly significant because Ca2+ signaling forms part of the signaling mechanisms by which T. gondii and other related pathogens, cause disease. In addition, essential parasite calcium signaling players can be developed as targets for anti-parasitic chemotherapy.Fluctuations of the cytosolic Ca2+ concentration regulate a variety of cellular functions in all eukaryotes. Ca2+ signaling starts by an increase in cytosolic Ca2+ that results from influx from the extracellular milieu or release from intracellular stores. The information encoded in transient Ca2+ signals is deciphered by various intracellular Ca2+ binding proteins (CBPs) that convert the signals into a wide variety of biochemical changes. CBPs bind Ca2+ through specific domains like the EF-hand domains composed of EF-hands. Calmodulin (CaM), with four EF hands plays a central role in Ca2+ signaling and it is the main mechanism by which Ca2+ signals are amplified to the scale of proteins and is transduced into biological responses. Binding of Ca2+ triggers a dramatic change in CaM shape favoring its interaction with target proteins resulting in diverse effects like relieve of autoinhibition, changes in domains structures, remodeling of active sites and also protein dimerization. In this proposal we aim at discovering new Ca2+ signaling players by exploring T. gondii CaM (TgCaM) binding sensors. Almost nothing is known about TgCaM and its downstream sensors, which most likely play essential roles in T. gondii by transducing information from Ca2+ signals. It is likely that some of the targets/sensors have been identified but the mechanistic basis for their activation, potentially by binding to TgCaM has not been shown. We believe that our work will lead to the discovery of novel bridging elements in the Ca2+ signaling cascade offering potentially novel chemotherapeutic targets. Additionally, the discovery of new protein players within established signaling pathways has the potential to generate novel insight into the early origins of complex signaling networks.

刚地弓形虫是专性细胞内寄生虫，在宿主细胞内复制。弓形虫属于