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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：
10318661
负责人：
Silvia N Moreno
金额：
$ 22.65万
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318661
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 Persons 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.

弓形虫是一种专性细胞内寄生虫，在宿主细胞内复制。T.弓形虫属于顶复门也包括许多医学和兽医相关的病原体。的这些疾病的临床表现是寄生虫在宿主细胞内生长的直接结果。复制和传播是T.弓形虫引起疾病。T.弓形虫参与多轮裂解循环，其由独特粘附素的附着和分泌组成，入侵宿主细胞，复制，外出和寻找另一个宿主细胞入侵。几乎所有这些生物细胞内游离钙（Ca 2+）的增加，随后刺激信号传导，这些级联的特征很不清楚。Ca 2+下游的许多转导元件要么不是已知或尚未表征，或者它们与信号级联中的其它元件的相互作用尚未清楚新信号元件的发现和表征非常重要，因为Ca 2+信号形成T.弓形虫和其他相关病原体，引起疾病。在此外，可以开发必需的寄生虫钙信号传导参与者作为抗寄生虫药物的靶点。细胞内Ca 2+浓度的波动调节各种细胞功能，真核生物Ca 2+信号传导开始于胞质Ca 2+的增加，这是由细胞外Ca 2+的流入引起的。环境或从细胞内储存释放。编码在瞬时Ca 2+信号中的信息被破译，各种细胞内Ca 2+结合蛋白（CBP），将信号转化为各种生物化学信号。变化CBP通过特定的结构域如由EF-手组成的EF-手结构域结合Ca 2+。钙调素（CaM）是一种具有四个EF手的蛋白质，在钙离子信号转导中起着核心作用，是介导细胞凋亡的主要机制。其中Ca 2+信号被放大到蛋白质的规模并被转换成生物反应。结合 Ca 2+触发CaM形状的急剧变化，有利于其与靶蛋白的相互作用，导致不同的蛋白质。如缓解自抑制、结构域结构改变、活性位点重塑以及蛋白质二聚化。在这个提议中，我们的目标是通过探索T.弓形虫钙调素（TgCaM）结合传感器。关于TgCaM及其下游传感器几乎一无所知，在T.通过Ca ~（2+）信号传递信息。很有可能，已经鉴定了靶/传感器，但是它们激活的机制基础，可能是通过结合到 TgCaM尚未显示。我们相信，我们的工作将导致发现新的桥接元件， Ca 2+信号级联提供了潜在的新的化疗靶点。此外，发现已建立的信号通路中的新蛋白质参与者有可能对信号通路产生新的见解。复杂信号网络的早期起源