Deciphering Molecular Mechanisms of Calcium Homeostasis
Deciphering Molecular Mechanisms of Calcium Homeostasis
批准号:
10796459
负责人:
Kenneth R Norman
金额:
$18.47万
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
项目状态:
未结题
起止时间:
2022-09-01 至 2027-08-31
关键词:
Alzheimer&aposs DiseaseBehavioral AssayBiological AssayBiological ModelsCaenorhabditis elegansCalciumCalcium SignalingCell DeathCell divisionCell physiologyDefectDiseaseEarly Onset Familial Alzheimer&aposs DiseaseEndoplasmic ReticulumFunctional disorderGenetic TranscriptionGoalsHealthHeart DiseasesHomeostasisHumanLysosomesMediatingMediatorMeditationMitochondriaMolecularMuscle ContractionMuscular DystrophiesMutationNecrosisNerve DegenerationNeurodegenerative DisordersNeuronsOrthologous GenePlantsProcessProteinsRNA interference screenRegulationResearch Project GrantsResolutionRoleStructureSynaptic VesiclesSystemage relatedcell typefitnessgene productgenetic manipulationinsightlive cell microscopymitochondrial metabolismmutantnovelpresenilinproteostasisuptakevesicular release
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Calcium is a critical mediator of many cellular processes, including muscle contraction,
mitochondrial activity, transcription, cell division, and synaptic vesicle release. Paradoxically,
calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium
signaling can disrupt cellular homeostasis. Consequently, calcium levels need to be tightly
controlled. Indeed, defective calcium signaling has been implicated in many neurodegenerative
diseases, muscular dystrophies and heart disease. To understand the mechanisms regulating
calcium signaling and how defects in this process can lead to cellular dysfunction, we are
exploiting the model system Caenorhabditis elegans to identify critical processes that are
involved in the regulation of calcium handling. We have recently demonstrated that SEL-12, the
C. elegans presenilin ortholog, has a role in mediating endoplasmic reticulum-mitochondrial
calcium homeostasis. Disruption of presenilin function results in an increase in mitochondrial
calcium levels and alters mitochondrial metabolism promoting protein homeostasis collapse and
neurodegeneration. Presenilin is a highly conserved protein found from plants to humans that is
extensively found on endomembrane structures (e.g., endoplasmic reticulum and lysosome) of
most cell types. However, the role presenilin has in the endomembrane system is not clear.
Importantly, mutations in human presenilin are the most common cause of early onset familial
Alzheimer's disease. Despite the identification of the involvement of presenilin in Alzheimer's
disease over 20 years ago, the functional consequences of mutations in presenilin causing
Alzheimer's disease are not understood. To gain further insight into the role presenilin has in
mitochondrial calcium homeostasis and neuronal fitness, we have developed a novel and highly
selective RNA interference screen to identify gene products that meditate the elevated
endoplasmic reticulum to mitochondrial calcium signaling observed in sel-12 mutants. From this
screen, we have identified several proteins known to mediate endoplasmic reticulum calcium
release and mitochondrial calcium uptake but we also identified several gene products with an
uncharacterized role in endoplasmic reticulum and mitochondrial calcium signaling. We propose
to utilize a multifaceted approach that combines genetic manipulation, high resolution live cell
microscopy to analyze endoplasmic reticulum and mitochondrial dynamics, mitochondrial
activity assays, and behavioral assays to determine the role these gene products as well as sel-
12 have in mitochondrial health and neuronal fitness.
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会议论文
Deciphering Molecular Mechanisms of Calcium Homeostasis
-
批准号:10406433
-
项目类别:
-
资助金额:$40.75万
-
财政年份:2022
-
负责人:Kenneth R Norman
-
依托单位:
Investigating the Molecular Mechanisms of Mitochondrial Calcium Uptake in Caenorhabditis elegans
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批准号:10286974
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项目类别:
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资助金额:$20.38万
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财政年份:2021
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负责人:Kenneth R Norman
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依托单位:
Investigating the Molecular Mechanisms of Mitochondrial Calcium Uptake in Caenorhabditis elegans
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批准号:10456980
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项目类别:
-
资助金额:$24.45万
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财政年份:2021
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负责人:Kenneth R Norman
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依托单位:
Investigation of calcium signaling in Caenorhabditis elegans
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批准号:8096801
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项目类别:
-
资助金额:$30.5万
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财政年份:2010
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负责人:Kenneth R Norman
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依托单位:
Investigation of calcium signaling in Caenorhabditis elegans
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批准号:8291070
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项目类别:
-
资助金额:$30.5万
-
财政年份:2010
-
负责人:Kenneth R Norman
-
依托单位:
Investigation of calcium signaling in Caenorhabditis elegans
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批准号:8683191
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项目类别:
-
资助金额:$30.5万
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财政年份:2010
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负责人:Kenneth R Norman
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依托单位:
Investigation of Calcium Signaling in Caenorhabditis elegans
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批准号:9893416
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项目类别:
-
资助金额:$6.69万
-
财政年份:2010
-
负责人:Kenneth R Norman
-
依托单位:
Investigation of Calcium Signaling in Caenorhabditis elegans
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批准号:9353426
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项目类别:
-
资助金额:$31.6万
-
财政年份:2010
-
负责人:Kenneth R Norman
-
依托单位:
Investigation of calcium signaling in Caenorhabditis elegans
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批准号:7993387
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项目类别:
-
资助金额:$29.22万
-
财政年份:2010
-
负责人:Kenneth R Norman
-
依托单位:
Investigation of calcium signaling in Caenorhabditis elegans
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批准号:8505496
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项目类别:
-
资助金额:$29.43万
-
财政年份:2010
-
负责人:Kenneth R Norman
-
依托单位:
国内基金
海外基金
新型F-18标记香豆素衍生物PET探针的研制及靶向Alzheimer's Disease 斑块显像研究
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批准号:81000622
-
项目类别:青年科学基金项目
-
资助金额:20.0万元
-
批准年份:2010
-
负责人:梁胜
-
依托单位:
阿尔茨海默病(Alzheimer's disease,AD)动物模型构建的分子机理研究
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批准号:31060293
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项目类别:地区科学基金项目
-
资助金额:26.0万元
-
批准年份:2010
-
负责人:郭亚芬
-
依托单位:
跨膜转运蛋白21(TMP21)对引起阿尔茨海默病(Alzheimer'S Disease)的γ分泌酶的作用研究
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批准号:30960334
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项目类别:地区科学基金项目
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资助金额:22.0万元
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批准年份:2009
-
负责人:董贵成
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依托单位: