Optogenetic toolkit for precise control of organellar calcium signaling
用于精确控制细胞器钙信号传导的光遗传学工具包
基本信息
- 批准号:10706462
- 负责人:
- 金额:$ 18.78万
- 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:2022-09-20 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AutophagocytosisBiomedical ResearchCalciumCalcium ChannelCalcium SignalingCardiovascular DiseasesCell Surface ReceptorsCell membraneCell physiologyCellular biologyCommunicationCouplingCytoplasmDiglyceridesDiseaseDrosophila melanogasterEndoplasmic ReticulumEnergy MetabolismEngineeringFRAP1 geneG-Protein-Coupled ReceptorsGenerationsGoalsHomeostasisInterventionKineticsLightLipidsLysosomesMalignant NeoplasmsMammalian CellMediatingMembraneMetabolic syndromeMitochondriaModificationMolecularMuscle CellsNamesNeurodegenerative DisordersOpticsOrganellesOuter Mitochondrial MembraneOxygenPathway interactionsPatternPerformancePhototoxicityPhysiological ProcessesPlayPositioning AttributePrecision therapeuticsPropertyProtein BiosynthesisProtein EngineeringProteinsReceptor Protein-Tyrosine KinasesResolutionRoleSTIM1 geneSarcoplasmic ReticulumSeriesShapesSideSignal TransductionSignaling MoleculeSiteSpecificitySystemTechnologyTestingToxic effectbiological systemsdesignendoplasmic reticulum stressextracellulargenetic manipulationhuman diseaseimmunoregulationin vivoinnovationinventionnervous system disorderneuroregulationnovelnovel strategiesoptogeneticsperoxisomepharmacologicprotein foldingrelease of sequestered calcium ion into cytoplasmremote controlresponsespatiotemporaltechnology developmenttoolultraviolet irradiationvoltage
项目摘要
Endoplasmic reticulum (ER), or sarcoplasmic reticulum in muscle cells, acts as the largest intracellular
Ca2+ store and plays a pivotal role in shaping the spatiotemporal dynamics of Ca2+ sigals to maintain
intracellular Ca2+ homeostasis. Reciprocally, calcium is also intimately involved in regulating ER functions,
including lipid synthesis, protein synthesis, folding, modifications and translocation. Consequently, the
ER employs a series of regulators to control Ca2+ concentration on both sides of the membrane and
mediate Ca2+ transfer with the surrounding organelles via membrane contact sites. Deregulated ER Ca2+
homeostasis not only results in ER stress and unfolded protein response (UPR), but also is involved in
cardiovascular diseases, neurological diseases, metabolic syndromes and other diseases.
Pharmacological modulation and genetic manipulations are often applied to study the ER Ca2+ handling
machinery, but these largely irreversible approaches often lack spatial precision and specificity.
Optogenetics technology provides a novel approach for modulating ER Ca2+ homeostasis with
superior spatiotemporal resolution and high reversibility. Hence, the team proposes to create an
innovative optogenetic toolkit, named as Genetically Encoded ER Calcium Actuators (GEECAs), that
enable optical interrogation of ER Ca2+ homeostasis, ER-organelle Ca2+ communications and organellar
Ca2+-modulated activities in multiple biological systems. In Specific Aim 1, the team will design a set of
GEECAs based on ER-localized calcium channels and/or their photoswitchable actuators to photo-tune
ER Ca2+ signals with varying kinetic and dynamic properties. In Specific Aim 2, the team seeks to develop
an optogenetic platform to control inter-organellar tethering and Ca2+ transfer between ER and its
surrounding organelles. The successful execution of this project will provide novel opportunities to
achieve noninvasive and precise modulation of ER Ca2+ homeostasis and inter-organellar Ca2+ signaling
with high spatiotemporal precision, thereby exerting remote control over cellular physiology, including ER
stress, energy metabolism, autophagy and mTOR signaling. From a translational perspective, molecular
tools generated from this project will provide novel interventional approaches for human diseases
associated with aberrant ER Ca2+ signaling.
内质网(ER),或肌肉细胞中的肌浆网,是细胞内最大的
Ca~(2+)的储存和维持在形成Ca~(2+)信号的时空动态中起着关键作用
细胞内钙离子动态平衡。反过来,钙也密切参与调节内质网功能,
包括脂质合成、蛋白质合成、折叠、修饰和易位。因此,
ER采用了一系列调节剂来控制膜两侧的钙离子浓度和
通过膜接触部位介导与周围细胞器的钙离子转移。去调节内质网钙离子
动态平衡不仅导致内质网应激和未折叠蛋白反应(UPR),而且还参与
心血管疾病、神经疾病、代谢综合征等疾病。
药物调控和遗传操作常被用于研究内质网钙离子的调节
但这些基本上不可逆转的方法往往缺乏空间精确度和特异性。
光遗传学技术为调控内质网钙稳态提供了一种新途径
优越的时空分辨率和高度的可逆性。因此,该团队提议创建一个
创新的光遗传工具包,名为遗传编码的ER钙执行器(GEECA),
启用内质网钙稳态、内质网钙通讯和细胞器的光学询问
钙离子在多种生物系统中的调节活性。在具体目标1中,团队将设计一套
基于内质网局部钙通道和/或其可光开关致动器的光可调GEECA
内质网钙信号具有不同的动力学和动力学性质。在具体目标2中,团队寻求开发
控制内质网和ITS间细胞器间拴系和钙离子转运的光遗传平台
周围的细胞器。该项目的成功实施将提供新的机会
实现内质网钙稳态和细胞器内钙信号的无创性精确调控
具有很高的时空精度,从而对包括内质网在内的细胞生理进行远程控制
压力、能量代谢、自噬和mTOR信号。从翻译的角度来看,分子
该项目产生的工具将为人类疾病提供新的干预方法
与内质网钙信号异常有关。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Shedding light on ORAI1 channel with genetic code expansion.
- DOI:10.1016/j.ceca.2023.102755
- 发表时间:2023-07
- 期刊:
- 影响因子:4
- 作者:Ali, Sher;Ma, Guolin;Zhou, Yubin
- 通讯作者:Zhou, Yubin
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$ 18.78万 - 项目类别:
Molecular control of calcium influx at the ER-plasma membrane junctions
内质网-质膜连接处钙内流的分子控制
- 批准号:
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- 资助金额:
$ 18.78万 - 项目类别:
Molecular control of calcium influx at the ER-plasma membrane junctions
内质网-质膜连接处钙内流的分子控制
- 批准号:
8765824 - 财政年份:2014
- 资助金额:
$ 18.78万 - 项目类别:
Molecular control of calcium influx at the ER-plasma membrane junctions
内质网-质膜连接处钙内流的分子控制
- 批准号:
9257436 - 财政年份:2014
- 资助金额:
$ 18.78万 - 项目类别:
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ER-血浆膜连接处钙流入的分子控制
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10386835 - 财政年份:2014
- 资助金额:
$ 18.78万 - 项目类别:
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