Regulation of host cell egress by Toxoplasma gondii
弓形虫对宿主细胞出口的调节
基本信息
- 批准号:10441782
- 负责人:
- 金额:$ 62.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-07 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:ActinsAdenylate CyclaseAdhesivesAuxinsBindingBiotinCRISPR/Cas technologyCalciumCalcium SignalingCell membraneCellsCodeConsumptionCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic GMPCyclic GMP-Dependent Protein KinasesDataDevelopmentDominant-Negative MutationDown-RegulationEquilibriumFosteringFoundationsFutureGenetic TranscriptionGoalsImmune systemImmunocompromised HostImpairmentIn VitroIndividualInfectionKnock-outKnowledgeLabelLigationLytic PhaseMass Spectrum AnalysisMediatingMembraneMolecularMotorMyosin ATPaseParasite ControlParasitesPathway interactionsPersonsPhenotypePhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPlayProcessProductionProtein IsoformsProteinsRegulationRiskRoleStructureTestingToxoplasmaToxoplasma gondiiToxoplasmosisactive controlbasecalcium-dependent protein kinasecell motilitychronic infectiondesignextracellularhuman diseasein vitro activityin vivoinhibitorknock-downmutantnovel therapeutic interventionphosphoproteomicsphosphoric diester hydrolaseprematurepreventprotein degradationprotein kinase A kinasetherapeutic developmentvalidation studies
项目摘要
Project Summary/Abstract
Active motility by apicomplexan parasites controls host cell invasion and egress, steps that are critical to the
intracellular cycle of infection. These processes are governed by calcium-regulated secretion of adhesive
proteins from micronemes, together with the concerted action of an actin-myosin motor that lies beneath the
parasite plasma membrane. Prior studies in Toxoplasma gondii have established the importance of calcium-
dependent protein kinases and protein kinase G (PKG) in controlling microneme secretion, motility, egress,
and invasion. This cascade is tightly regulated and recent studies have also shown that the c1 isoform of
protein kinase A (PKAc1) dampens calcium signaling to shut down microneme secretion and impair motility
after invasion is complete. The balance between PKG vs. PKAc1 activities governs the decision to activate
motility and promote egress vs. to remain intracellular. Although the role of PKAc1 in blocking premature
egress is clear, neither its mechanism of regulation nor the targets that it phosphorylates in order to dampen
calcium signaling and block egress have been elucidated. PKA activity is governed by production of cyclic
AMP (cAMP) by adenylate cyclases (ACs) and its consumption by phosphodiesterases (PDEs). In preliminary
studies, we have identified candidate ACs that control cAMP levels to regulate PKA. In the proposed studies,
we will explore their functions to define how they temporally and spatially regulate PKA activity. We have also
used a protein degradation approach to create conditional knockdowns of PKA isoforms and verify that PKAc1
controls egress in type II parasites. We will use the tightly regulated conditional knockdown approach to
investigate downstream targets of PKAc1 that mediate the egress block using a combination of
phosphoproteomic studies to identify substrates and downstream validation studies to test their roles in
regulating egress. We will validate the role of specific phosphorylation sites in PKAc1 targets in suppressing
calcium signaling, motility, and egress. Collectively, the proposed studies will elucidate the molecular pathway
by which PKAc1 down regulates calcium levels, microneme secretion, and motility to prevent egress, thus
counterbalancing the activating effects of PKG. Elucidating the molecular regulation of the PKG/PKA kinases in
T. gondii will foster future studies to design inhibitors that block these pathways, thus providing new avenues
for development of therapeutics.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
L. David Sibley其他文献
ワークショップ 本邦におけるトキソプラズマ分離株の分子タイピング
日本弓形虫分离株的分子分型研讨会
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
永宗喜三郎;喜屋武向子;山本徳栄;山野安規徳;Asis Khan;L. David Sibley - 通讯作者:
L. David Sibley
Protozoan persister-like cells and drug treatment failure
原生动物类持久性细胞与药物治疗失败
- DOI:
10.1038/s41579-019-0238-x - 发表时间:
2019-08-23 - 期刊:
- 影响因子:103.300
- 作者:
Michael P. Barrett;Dennis E. Kyle;L. David Sibley;Joshua B. Radke;Rick L. Tarleton - 通讯作者:
Rick L. Tarleton
A combination of four emToxoplasma gondii/em nuclear-targeted effectors protects against interferon gamma-driven human host cell death
四种针对弓形虫核的效应蛋白的组合可防止干扰素γ驱动的人类宿主细胞死亡
- DOI:
10.1128/mbio.02124-24 - 发表时间:
2024-08-30 - 期刊:
- 影响因子:4.700
- 作者:
Brittany Henry;Aubrey J. Phillips;L. David Sibley;Alex Rosenberg - 通讯作者:
Alex Rosenberg
Cerebral Malaria Is Regulated by Host-Mediated Changes in emPlasmodium/em Gene Expression
脑型疟疾受宿主介导的疟原虫基因表达变化调节
- DOI:
10.1128/mbio.03391-22 - 发表时间:
2023-04-10 - 期刊:
- 影响因子:4.700
- 作者:
Clare K. Cimperman;Mirna Pena;Sohret M. Gokcek;Brandon P. Theall;Meha V. Patel;Anisha Sharma;ChenFeng Qi;Daniel Sturdevant;Louis H. Miller;Patrick L. Collins;Susan K. Pierce;Munir Akkaya;L. David Sibley - 通讯作者:
L. David Sibley
No more free lunch
天下没有免费的午餐
- DOI:
10.1038/415843a - 发表时间:
2002-02-21 - 期刊:
- 影响因子:48.500
- 作者:
L. David Sibley - 通讯作者:
L. David Sibley
L. David Sibley的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('L. David Sibley', 18)}}的其他基金
Regulation of host cell egress by Toxoplasma gondii
弓形虫对宿主细胞出口的调节
- 批准号:
10640220 - 财政年份:2022
- 资助金额:
$ 62.16万 - 项目类别:
Interferon-mediated control mechanisms in human cells
人类细胞中干扰素介导的控制机制
- 批准号:
10041166 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别:
Interferon-mediated control mechanisms in human cells
人类细胞中干扰素介导的控制机制
- 批准号:
10194376 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别:
Effect of Microbial Metabolites on Growth of Cryptosporidium
微生物代谢产物对隐孢子虫生长的影响
- 批准号:
9927337 - 财政年份:2019
- 资助金额:
$ 62.16万 - 项目类别:
Effect of Microbial Metabolites on Growth of Cryptosporidium
微生物代谢产物对隐孢子虫生长的影响
- 批准号:
10303025 - 财政年份:2019
- 资助金额:
$ 62.16万 - 项目类别:
Effect of Microbial Metabolites on Growth of Cryptosporidium
微生物代谢产物对隐孢子虫生长的影响
- 批准号:
10527363 - 财政年份:2019
- 资助金额:
$ 62.16万 - 项目类别:
INHIBITION OF STAT TRANSCRIPTION BY TOXOPLASMA
弓形虫对 STAT 转录的抑制
- 批准号:
9244190 - 财政年份:2016
- 资助金额:
$ 62.16万 - 项目类别:
相似海外基金
Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade
能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
- 批准号:
RGPIN-2021-04040 - 财政年份:2022
- 资助金额:
$ 62.16万 - 项目类别:
Discovery Grants Program - Individual
Controlled Release of Pituitary Adenylate Cyclase Activating Polypeptide from a Hydrogel-Nanoparticle Delivery Vehicle for Applications in the Central Nervous System
从水凝胶-纳米粒子递送载体中控制释放垂体腺苷酸环化酶激活多肽,用于中枢神经系统的应用
- 批准号:
547124-2020 - 财政年份:2022
- 资助金额:
$ 62.16万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Controlled Release of Pituitary Adenylate Cyclase Activating Polypeptide from a Hydrogel-Nanoparticle Delivery Vehicle for Applications in the Central Nervous System
从水凝胶-纳米粒子递送载体中控制释放垂体腺苷酸环化酶激活多肽,用于中枢神经系统的应用
- 批准号:
547124-2020 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Postgraduate Scholarships - Doctoral
Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade
能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
- 批准号:
RGPIN-2021-04040 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Discovery Grants Program - Individual
The Molecular Mechanism of the Secretion of the Bacterial Toxin Adenylate Cyclase
细菌毒素腺苷酸环化酶分泌的分子机制
- 批准号:
451966 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Operating Grants
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
- 批准号:
10261394 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别:
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
- 批准号:
10455587 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别:
Diagnosis and therapeutic effect of neurally mediated syncope (NMS) using fluctuation of adenylate cyclase activity
利用腺苷酸环化酶活性波动对神经介导性晕厥(NMS)的诊断和治疗效果
- 批准号:
20K08498 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Pituitary adenylate cyclase-activating polypeptide 27 in the paraventricular thalamus and its projections: Role in ethanol drinking
室旁丘脑中的垂体腺苷酸环化酶激活多肽 27 及其预测:在乙醇饮用中的作用
- 批准号:
10380126 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别:
The role of prefrontostriatal Pituitary Adenylate Cyclase Activating Polypeptide in excessive and compulsive ethanol drinking
前额纹状体垂体腺苷酸环化酶激活多肽在过量和强迫性乙醇饮酒中的作用
- 批准号:
10662279 - 财政年份:2020
- 资助金额:
$ 62.16万 - 项目类别: