The Toxoplasma apicoplast and calcium signaling
The Toxoplasma apicoplast and calcium signaling
批准号:
10051384
负责人:
Silvia N Moreno
金额:
$37.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-11-10 至 2022-10-31
关键词:
AffectAlgaeAmino AcidsAnimalsAntiparasitic AgentsApicomplexaBiological ModelsBiological ProcessCalciumCalcium SignalingCationsCellsCommunicationComplementCoupledCyanobacteriumDefectDevelopmentDiagnosticDown-RegulationElectrophysiology (science)EndosomesEnvironmentEnzymesGenesGoalsGrowthHomeostasisIon ChannelIon Channel GatingIonsLaboratoriesLifeLysosomesMammalian CellMedicalMembraneMetalsModelingMutationNAADPOrganellesParasitesPathway interactionsPhysiologicalPhysiologyPlantsPlastidsPlayProcessPropertyProteinsRegulationReportingRoleSecond Messenger SystemsSignal TransductionTRP channelTherapeuticToxoplasmaToxoplasma gondiiTransmembrane DomainVaccinesVacuoleWorkbiophysical techniquescalcium indicatorchemotherapyfitnessmicroorganismmutantnovelnovel therapeuticspathogentherapeutic targetuptakevoltage
中文摘要
顶复门寄生虫包括许多具有医学和兽医重要性的病原体,
长期目标是鉴定这些微生物中的新分子和途径,
化疗、诊断应用或疫苗。
这些寄生虫中的许多依赖于在残余质体中发生的生物合成途径来生存
称为顶质体。大量的这些合成代谢途径对寄生虫的生活至关重要。
我们的实验室最近发现了一个双孔通道(TPC),它定位于顶质体膜,
对刚地弓形虫的生长至关重要。双孔通道属于电压门控离子超家族
通道,其特征在于存在两组六跨膜结构域(TMD)。这是
这是一个重要的发现,因为它揭示了一个完全未开发的问题,即像Ca2+这样的离子的作用,
对细胞器的必需合成代谢酶的活性以及这如何影响寄生虫适应性的影响。在
此外,更重要的是,离子通道是许多治疗上有用的药剂的靶标,
作为治疗靶点,甚至作为抗寄生虫剂,仍然显著开发不足。
顶质体是次级内共生过程的产物,是一种被
细胞膜来源于蓝细菌,是质体、内共生菌和
宿主内体区室。金属离子对三分之一以上的活性起着至关重要的作用,
酶和考虑到大量的必需活动存在于顶质体,它很可能是离子
会在细胞器中受到高度调控在顶质体中还没有离子转运体或通道的报道
到现在
这使得我们最近发现的一个位于顶质体的双孔通道成为一个独特的发现,
这也是开发新疗法的一个意想不到的机会。TPC在动物和哺乳动物中均存在,
在植物细胞中,它们定位于酸性细胞器,如内体、溶酶体和液泡。TPCs
在哺乳动物细胞中作为Ca2+通道起作用,并被第二信使烟酸激活
腺嘌呤二核苷酸磷酸(NAADP)。弓形虫TPC定位于质体是唯一的,
Apicomplexa和突出了一个新的和潜在的具体作用的细胞器的多种功能。
我们让T沉默了弓形虫TgTPC基因,发现突变体显示出严重的生长缺陷,
通过与功能通道互补来拯救。我们的假设是TPC是一种非选择性的
在电压门控时能够传导阳离子的通道,但在细胞的环境中,
偏好Ca2+。这一假设意味着顶质体含有Ca2+,初步研究结果支持这一观点。
证据我们提出了一个模型,其中顶质体通过TPC和Ca 2+与其他细胞通讯,
细胞器通过其他潜在的Ca2+通道。将研究另外两个候选Ca2+通道。
我们的目标是使用复杂的生物物理学方法来定义TgTPC的生理功能。
在几个模型系统的范围内的方法。我们将联合收割机与活细胞研究相结合,
确定它们的活性如何影响顶质体和其他细胞内
细胞器和寄生虫的适应性。
英文摘要
Apicomplexan parasites include a number of pathogens of medical and veterinary importance and our long-
term goal is to identify novel molecules and pathways in these microorganisms that could be targets for
chemotherapy, diagnostic applications, or vaccines.
Many of these parasites rely for their survival on biosynthetic pathways that occur in a remnant plastid
known as the apicoplast. A large number of these anabolic pathways are essential for the life of the parasite.
Our laboratory recently found a two-pore channel (TPC) that localizes to the apicoplast membrane(s) and is
essential for growth of Toxoplasma gondii. Two-pore channels belong to the superfamily of voltage-gated ion
channels and are characterized by the presence of two sets of six-transmembrane domains (TMDs). This was
an important discovery because it exposed a completely untapped question, which is the role of ions like Ca2+
on the activity of essential anabolic enzymes of the organelle and how this impacts parasite fitness. In
addition, and more importantly, ion channels are targets of many therapeutically useful agents and they
remain significantly under-exploited as therapeutic targets, even more so as antiparasitic agents.
The apicoplast, the product of a secondary endosymbiosis process, is an organelle surrounded by
membranes derived from the cyanobacterium that gave origin to the plastid, the endosymbiotic alga, and the
host endosomal compartment. Metal ions play essential roles for the activity of more than one third of all
enzymes and considering the large number of essential activities present in the apicoplast, it is likely that ions
will be highly regulated in the organelle. No ion transporters or channels have been reported in the apicoplast
until now.
This makes our recent discovery of a two-pore channel localized to the apicoplast a unique finding and
also an unexpected opportunity for the development of new therapies. TPCs are found in both animal and
plant cells where they localize to acidic organelles such as endosomes, lysosomes and vacuoles. TPCs
function as Ca2+ channels in mammalian cells and are activated by the second messenger nicotinic acid
adenine dinucleotide phosphate (NAADP). The Toxoplasma TPC localization to the plastid is unique to
Apicomplexa and highlights a novel and potentially specific role for the organelle multiple functions.
We silenced the T. gondii TgTPC gene and found that the mutants display a severe growth defect that can
be rescued by complementation with a functional channel. Our hypothesis is that the TPC is a non-selective
channel that upon voltage gating is able to conduct cations but in the environment of the cell it probably
prefers Ca2+. This hypothesis implies that the apicoplast contains Ca2+, an idea supported by preliminary
evidence. We propose a model in which the apicoplast through the TPC and Ca2+ communicates with other
organelles via other potential Ca2+ channels. Two other candidate Ca2+ channels will be studied.
Our goal is to define the physiological function of TgTPC using sophisticated biophysical
approaches in the context of several model systems. We will combine this with live cell studies to
determine how their activity influences the physiology of the apicoplast and other intracellular
organelles and the fitness of the parasite.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.mib.2021.09.002
发表时间:
2021-12
期刊:
Current opinion in microbiology
影响因子:
5.4
作者:
[Docampo R, Moreno SN]
通讯作者:
Moreno SN
DOI:
10.1111/jeu.12675
发表时间:
2019-03
期刊:
The Journal of eukaryotic microbiology
影响因子:
--
作者:
[Chang L, Dykes EJ, Li J, Moreno SNJ, Hortua Triana MA]
通讯作者:
Hortua Triana MA
The role of polyphosphate in Toxoplasma gondii
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批准号:10681078
-
项目类别:
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资助金额:$21.28万
-
财政年份:2023
-
负责人:Silvia N Moreno
-
依托单位:
Divergent Calcium Channels of the Apicomplexan parasite Toxoplasma gondii
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批准号:10681807
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项目类别:
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资助金额:$62.48万
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财政年份:2023
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负责人:Silvia N Moreno
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依托单位:
Validation of the ubiquinone synthesis pathway of Toxoplasma gondii as a novel drug target
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批准号:10608408
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项目类别:
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资助金额:$41.57万
-
财政年份:2022
-
负责人:Silvia N Moreno
-
依托单位:
Validation of the ubiquinone synthesis pathway of Toxoplasma gondii as a novel drug target
-
批准号:10707505
-
项目类别:
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资助金额:$43.11万
-
财政年份:2022
-
负责人:Silvia N Moreno
-
依托单位:
Elements of the Ca2+ signal transduction pathway of Toxoplasma gondii
-
批准号:10154355
-
项目类别:
-
资助金额:$18.88万
-
财政年份:2020
-
负责人:Silvia N Moreno
-
依托单位:
Anti-Toxoplasma isoprenoid pathway inhibitors and the host immune response
-
批准号:10117182
-
项目类别:
-
资助金额:$22.65万
-
财政年份:2020
-
负责人:Silvia N Moreno
-
依托单位:
Elements of the Ca2+ signal transduction pathway of Toxoplasma gondii
-
批准号:10318661
-
项目类别:
-
资助金额:$22.65万
-
财政年份:2020
-
负责人:Silvia N Moreno
-
依托单位:
Regulation of calcium signaling in the human malaria parasite
-
批准号:9759759
-
项目类别:
-
资助金额:$18.88万
-
财政年份:2018
-
负责人:Silvia N Moreno
-
依托单位:
The Toxoplasma apicoplast and calcium signaling
-
批准号:9384713
-
项目类别:
-
资助金额:$37.5万
-
财政年份:2016
-
负责人:Silvia N Moreno
-
依托单位:
The Toxoplasma apicoplast and calcium signaling
-
批准号:9229418
-
项目类别:
-
资助金额:$37.5万
-
财政年份:2016
-
负责人:Silvia N Moreno
-
依托单位:
Genetically Encoded Calcium Indicators in Toxoplasma gondii
-
批准号:8874890
-
项目类别:
-
资助金额:$18.75万
-
财政年份:2014
-
负责人:Silvia N Moreno
-
依托单位:
Genetically Encoded Calcium Indicators in Toxoplasma gondii
-
批准号:8786763
-
项目类别:
-
资助金额:$22.35万
-
财政年份:2014
-
负责人:Silvia N Moreno
-
依托单位:
Targeting Host and Apicomplexan Isoprenoid Pathways
-
批准号:8496713
-
项目类别:
-
资助金额:$22.28万
-
财政年份:2012
-
负责人:Silvia N Moreno
-
依托单位:
Targeting Host and Apicomplexan Isoprenoid Pathways
-
批准号:9089810
-
项目类别:
-
资助金额:$43.48万
-
财政年份:2012
-
负责人:Silvia N Moreno
-
依托单位:
Targeting Host and Apicomplexan Isoprenoid Pathways
-
批准号:8853603
-
项目类别:
-
资助金额:$43.48万
-
财政年份:2012
-
负责人:Silvia N Moreno
-
依托单位:
Targeting Host and Apicomplexan Isoprenoid Pathways
-
批准号:8391318
-
项目类别:
-
资助金额:$18.56万
-
财政年份:2012
-
负责人:Silvia N Moreno
-
依托单位:
Targeting Host and Apicomplexan Isoprenoid Pathways
-
批准号:8890100
-
项目类别:
-
资助金额:$43.48万
-
财政年份:2012
-
负责人:Silvia N Moreno
-
依托单位:
The plant-like vacuole of Toxoplasma gondii
-
批准号:8385516
-
项目类别:
-
资助金额:$34.9万
-
财政年份:2011
-
负责人:Silvia N Moreno
-
依托单位:
The plant-like vacuole of Toxoplasma gondii
-
批准号:8585022
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2011
-
负责人:Silvia N Moreno
-
依托单位:
The plant-like vacuole of Toxoplasma gondii
-
批准号:8258564
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2011
-
负责人:Silvia N Moreno
-
依托单位:
海外基金