Calcium/ Calmodulin Activated Kinases in Smooth Muscle
Calcium/ Calmodulin Activated Kinases in Smooth Muscle
批准号:
10705334
负责人:
HAROLD A SINGER
金额:
$58.29万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1994
资助国家:
美国
项目状态:
已结题
起止时间:
1994-07-01 至 2024-08-31
关键词:
Abdominal Aortic AneurysmAffectAlternative SplicingAmino Acid SequenceAngiotensin IIAntisense OligonucleotidesAortic AneurysmApoptosisArterial InjuryBlood VesselsC-terminalCalciumCalcium SignalingCalmodulinCalmodulin 1Carotid Artery InjuriesCell ProliferationCell physiologyCellsClinicalCollaborationsComplexCytosineDataDependenceDiseaseEndothelial CellsEndotheliumEpigenetic ProcessExonsExtracellular MatrixFYN geneGenesGenetic TranscriptionGenetically Engineered MouseGoalsGrowth FactorHeart HypertrophyHeart failureHoloenzymesHumanHyperplasiaIn VitroIndividualInflammatoryInfusion proceduresInjuryIsoenzymesKnock-outKnowledgeMedialMediatingModelingMolecular GeneticsMusMuscle functionOligonucleotidesPathologicPathway interactionsPhenotypePhosphotransferasesProtein IsoformsProteinsPublishingRIPK3 geneRNA SplicingRegulationReportingResearch Project GrantsRoleSTAT3 geneSerineSignal TransductionSmooth MuscleSmooth Muscle MyocytesStentsStimulusStructureTNF geneTestingTherapeuticThreonineTimeTransducersUmbilical veinUniversitiesVariantVascular DiseasesVascular Endothelial CellVascular EndotheliumVascular Smooth MuscleVascular remodelingWisconsinarterial remodelingbasecalmodulin-dependent protein kinase IIcell growth regulationcell motilitycell typechemokineconditional knockoutdemethylationdesignendothelial regenerationexon skippingfemoral arterygenetic approachin vivoinflammatory milieumechanical stimulusmigrationmouse modelnovelnovel therapeutic interventionpromoterresponseresponse to injuryrestenosissensorvascular injuryvascular smooth muscle cell proliferationwound healing
中文摘要
项目概述:这个正在进行的研究项目旨在定义多功能的功能
英文摘要
Project Summary: This ongoing research project is aimed at defining functions of multi-functional
serine/threonine Ca2+/Calmodulin-dependent protein kinase II (CaMKII) isozymes in injury- and disease-
induced vascular remodeling. CaMKII is structurally complex and is expressed as a large hetero-multimeric
holoenzyme with 12-14 individual kinase subunits. CAMK2 genes undergo extensive alternative splicing to
produce variants that can affect holoenzyme subcellular localization and protein interactions. The central
hypothesis is that cell-specific expression and activation of CaMKII isoforms and splice variants are functional
determinants of integrated vascular remodeling in response to injury and disease.
The first specific aim extends our expertise in CaMKII structure and function in vascular smooth muscle to the
vascular endothelium, in the context of an in vivo mouse model of intraluminal arterial injury that simulates
aspects of in-stent restenosis. The functions of vascular endothelial cell CaMKII isoforms in re-
endothelialization following intraluminal injury are tested by conditional knockout of specific Camk2 genes in
genetically engineered mice. Regulation of the CaMKII isoform by STAT3 and the role of CaMKII in
mediating STAT3-dependent functions are tested in this inflammatory environment. The second specific aim
capitalizes on knowledge of CaMKII variant expression in vascular smooth muscle and tests the functional
significance of an alternatively spliced c-terminal amino acid sequence in CaMKIIthat mediates formation of a
CaMKII/Fyn complex, and subsequent regulation of cellular processes involved in vascular smooth muscle
cell motility and proliferation A novel CaMKII antisense exon-skipping oligonucleotide (ESO) approach,
designed to precisely interfere with expression of this sequence has been validated in vitro. ESOs will be
administered to mice prior to intraluminal arterial injury with the goal of limiting vascular smooth muscle
migration to the intima and subsequent neointimal hyperplasia, without affecting vasculoprotective endothelial
regeneration. The final aim investigates the function of CaMKII isoforms in promoting programmed cell death
by necroptosis in vascular smooth muscle and the role of this mechanism is promoting progression of
abdominal aortic aneurysm. This aim is carried out in collaboration with labs at Augusta University and the
University of Wisconsin and is investigated using mouse models of aortic aneurysm and conditional knockout
of specific Camk2 genes in vascular smooth muscle.
Relevance: Accomplishing these aims will provide detailed information on the functional importance of specific
CaMKII isoform variants in vascular injury, in stent-restenosis and aneurysmal disease. Application of
antisense ESOs targeting CaMKII may provide novel therapeutic approaches to mitigate progression of
vascular disease.
期刊论文(17)
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Type-3 ryanodine receptors mediate hypoxia-, but not neurotransmitter-induced calcium release and contraction in pulmonary artery smooth muscle cells.
3型ryanodine受体介导缺氧 - 但没有神经递质诱导的钙释放和肺动脉平滑肌细胞的收缩。
DOI:
10.1085/jgp.200409232
发表时间:
2005-04
期刊:
JOURNAL OF GENERAL PHYSIOLOGY
影响因子:
3.8
作者:
[Zheng, Yun-Min, Wang, Qing-Song, Rathore, Rakesh, Zhang, Wan-Hui, Mazurkiewicz, Joseph E, Sorrentino, Vincenzo, Singer, Harold A, Kotlikoff, Michael I, Wang, Yong-Xiao]
通讯作者:
Wang, Yong-Xiao
DOI:
10.1016/j.molmet.2021.101300
发表时间:
2021-11
期刊:
Molecular metabolism
影响因子:
8.1
作者:
[Dai W, Choubey M, Patel S, Singer HA, Ozcan L]
通讯作者:
Ozcan L
DOI:
10.1152/ajpcell.2000.278.3.c537
发表时间:
2000-03
期刊:
American journal of physiology. Cell physiology
影响因子:
--
作者:
[A. Rokolya;H. Singer]
通讯作者:
A. Rokolya;H. Singer
DOI:
10.1016/j.freeradbiomed.2012.09.026
发表时间:
2013-01
期刊:
FREE RADICAL BIOLOGY AND MEDICINE
影响因子:
7.4
作者:
[Ginnan, Roman, Jourd'heuil, Frances L., Guikema, Benjamin, Simons, Malorie, Singer, Harold A., Jourd'heuil, David]
通讯作者:
Jourd'heuil, David
Novel Ca2+/calmodulin-dependent protein kinase II gamma-subunit variants expressed in vascular smooth muscle, brain, and cardiomyocytes.
在血管平滑肌、大脑和心肌细胞中表达的新型 Ca2/钙调蛋白依赖性蛋白激酶 II γ 亚基变体。
DOI:
10.1074/jbc.272.14.9393
发表时间:
1997
期刊:
The Journal of biological chemistry
影响因子:
--
作者:
[Singer,HA, Benscoter,HA, Schworer,CM]
通讯作者:
Schworer,CM
共 7 条
Control of Vascular Cell Motility by CaMKII
-
批准号:8235852
-
项目类别:
-
资助金额:$39.11万
-
财政年份:2010
-
负责人:HAROLD A SINGER
-
依托单位:
Control of Vascular Cell Motility by CaMKII
-
批准号:7899534
-
项目类别:
-
资助金额:$39.5万
-
财政年份:2010
-
负责人:HAROLD A SINGER
-
依托单位:
Control of Vascular Cell Motility by CaMKII
-
批准号:8043594
-
项目类别:
-
资助金额:$39.5万
-
财政年份:2010
-
负责人:HAROLD A SINGER
-
依托单位:
Control of Vascular Cell Motility by CaMKII
-
批准号:8424244
-
项目类别:
-
资助金额:$37.23万
-
财政年份:2010
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:7822181
-
项目类别:
-
资助金额:$1.57万
-
财政年份:2009
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
-
批准号:2225510
-
项目类别:
-
资助金额:$19.72万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
-
批准号:2709135
-
项目类别:
-
资助金额:$19.82万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINIASES IN SMOOTH MUSCLE
-
批准号:6638340
-
项目类别:
-
资助金额:$31.0万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:6890456
-
项目类别:
-
资助金额:$35.55万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:8449739
-
项目类别:
-
资助金额:$36.99万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:8063208
-
项目类别:
-
资助金额:$39.25万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:8270015
-
项目类别:
-
资助金额:$38.86万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
-
批准号:2225512
-
项目类别:
-
资助金额:$19.08万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:7674461
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项目类别:
-
资助金额:$39.25万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINIASES IN SMOOTH MUSCLE
-
批准号:6389253
-
项目类别:
-
资助金额:$31.0万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:7050551
-
项目类别:
-
资助金额:$34.71万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:6821491
-
项目类别:
-
资助金额:$35.55万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
-
批准号:2225511
-
项目类别:
-
资助金额:$20.21万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
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批准号:6192264
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项目类别:
-
资助金额:$31.0万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
-
批准号:2848538
-
项目类别:
-
资助金额:$21.43万
-
财政年份:1994
-
负责人:HAROLD A SINGER
-
依托单位:
海外基金