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:这项正在进行的研究项目旨在定义多功能的功能
损伤和疾病中的丝氨酸/苏氨酸钙/钙调素依赖的蛋白激酶II(CaMKII)同工酶
诱导血管重塑。CaMKII结构复杂,表现为一个大的异源多聚体
含有12-14个单独的激酶亚基的全酶。CaMK2基因经历了广泛的选择性剪接
产生能够影响全酶、亚细胞定位和蛋白质相互作用的变体。中环
假设CaMKII亚型和剪接变异体的细胞特异性表达和激活具有功能性
损伤和疾病反应中综合血管重塑的决定因素。
第一个具体目标是将我们在血管平滑肌CaMKII结构和功能方面的专业知识扩展到
血管内皮细胞,在模拟动脉腔内损伤的活体小鼠模型的背景下
支架内再狭窄的一些方面。血管内皮细胞CaMKII亚型在心肌梗死中的作用
血管内损伤后的内皮化通过有条件地敲除特定的CaMK2基因来测试
转基因小鼠。STAT3对CaMKII异构体的调控及其在细胞周期调控中的作用
介导STAT3依赖的功能在这种炎症环境中进行了测试。第二个具体目标
利用CaMKII在血管平滑肌中变异表达的知识,并测试其功能
CaMKII中选择性剪接的c-末端氨基酸序列在调节a的形成中的意义
CaMKII/FYN复合体及其对血管平滑肌细胞过程的调控
细胞运动和增殖一种新的CaMKII反义外显子跳过寡核苷酸方法,
设计的精确干扰该序列的表达已在体外得到验证。国有企业将成为
在小鼠动脉腔内损伤前给药,目的是限制血管平滑肌
迁移至内膜和随后的新生内膜增生,而不影响血管保护性内皮
再生。最终目的是研究CaMKII亚型在促进细胞程序性死亡中的作用
通过血管平滑肌的坏死性下垂,其作用机制是促进血管病变的进展
腹主动脉瘤。这一目标是与奥古斯塔大学的实验室和
并使用主动脉瘤和条件性基因敲除的小鼠模型进行研究
血管平滑肌中特异的CaMK2基因。
相关性:实现这些目标将提供有关特定功能重要性的详细信息
CaMKII亚型变异在血管损伤、支架再狭窄和动脉瘤疾病中的作用。应用程序
针对CaMKII的反义ESO可能提供新的治疗方法来减缓肿瘤的进展
血管疾病。
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.
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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 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: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: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:2709135
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项目类别:
-
资助金额:$19.82万
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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
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项目类别:
-
资助金额:$39.25万
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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
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财政年份:1994
-
负责人:HAROLD A SINGER
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依托单位:
Calcium/Calmodulin Activated Kinases in Smooth Muscle
-
批准号:8270015
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项目类别:
-
资助金额:$38.86万
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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:2225512
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项目类别:
-
资助金额:$19.08万
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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
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批准号:6389253
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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:7050551
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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
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批准号:6821491
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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:2848538
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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:
CALCIUM/CALMODULIN ACTIVATED KINASES IN SMOOTH MUSCLE
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批准号:2225511
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项目类别:
-
资助金额:$20.21万
-
财政年份:1994
-
负责人:HAROLD A SINGER
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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:
海外基金