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Calcium/ Calmodulin Activated Kinases in Smooth Muscle

平滑肌中的钙/钙调蛋白激活激酶

基本信息

批准号：
10705334
负责人：
HAROLD A SINGER
金额：
$ 58.29万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705334
关键词：
Abdominal Aortic Aneurysm Affect Alternative Splicing Amino Acid Sequence Angiotensin II Antisense Oligonucleotides Aortic Aneurysm Apoptosis Arterial Injury Blood Vessels C-terminal Calcium Calcium Signaling Calmodulin Calmodulin 1 Carotid Artery Injuries Cell Proliferation Cell physiology Cells Clinical Collaborations Complex Cytosine Data Dependence Disease Endothelial Cells Endothelium Epigenetic Process Exons Extracellular Matrix FYN gene Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Factor Heart Hypertrophy Heart failure Holoenzymes Human Hyperplasia In Vitro Individual Inflammatory Infusion procedures Injury Isoenzymes Knock-out Knowledge Medial Mediating Modeling Molecular Genetics Mus Muscle function Oligonucleotides Pathologic Pathway interactions Phenotype Phosphotransferases Protein Isoforms Proteins Publishing RIPK3 gene RNA Splicing Regulation Reporting Research Project Grants Role STAT3 gene Serine Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stents Stimulus Structure TNF gene Testing Therapeutic Threonine Time Transducers Umbilical vein Universities Variant Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular Smooth Muscle Vascular remodeling Wisconsin arterial remodeling base calmodulin-dependent protein kinase II cell growth regulation cell motility cell type chemokine conditional knockout demethylation design endothelial regeneration exon skipping femoral artery genetic approach in vivo inflammatory milieu mechanical stimulus migration mouse model novel novel therapeutic intervention promoter response response to injury restenosis sensor vascular injury vascular smooth muscle cell proliferation wound healing

项目摘要

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 CaMKIIthat 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.

项目概述：这个正在进行的研究项目旨在定义多功能丝氨酸/苏氨酸Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）同工酶在损伤和疾病中的作用诱导血管重塑。CaMKII结构复杂，表达为一个大的异源多聚体，全酶具有12-14个单独的激酶亚基。CAMK 2基因经历广泛的选择性剪接，产生可以影响全酶亚细胞定位和蛋白质相互作用的变体。中央假设CaMK II同种型和剪接变体细胞特异性表达和活化是功能性的损伤和疾病后血管重塑的决定因素。第一个具体目标将我们在血管平滑肌中CaMKII结构和功能的专业知识扩展到血管内皮，在模拟管腔内动脉损伤的体内小鼠模型的情况下，支架内再狭窄方面。血管内皮细胞CaMKII亚型在再灌注损伤中的作用通过条件性敲除特定的Camk 2基因来测试管腔内损伤后的内皮化。基因工程小鼠STAT 3对CaMKII亚型的调节及CaMKII亚型在细胞凋亡中的作用在这种炎症环境中测试介导STAT 3依赖性功能。第二个具体目标利用血管平滑肌中CaMKII变体表达的知识，并测试功能性 CaMKII激酶C末端可变剪接氨基酸序列在介导细胞凋亡形成中的意义 CaMKII κ B/Fyn复合物，以及随后参与血管平滑肌的细胞过程的调节细胞运动和增殖一种新的CaMKII反义外显子跳跃寡核苷酸（ESO）方法，设计用于精确干扰该序列的表达的方法已经在体外得到验证。ESO将是在管腔内动脉损伤之前给予小鼠，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细胞再生最后的目的是研究CaMKII亚型在促进程序性细胞死亡中的功能通过血管平滑肌的坏死性凋亡，这种机制的作用是促进腹主动脉瘤.这一目标是与奥古斯塔大学的实验室合作实现的，威斯康星州的研究，并使用小鼠模型的主动脉瘤和条件敲除血管平滑肌中的特异性Camk 2基因。相关性：实现这些目标将提供关于特定功能重要性的详细信息。血管损伤、支架再狭窄和血管系统疾病中的CaMKII β亚型变体的应用靶向CaMKII β的反义ESO可能提供新的治疗方法，以减轻血管疾病

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

Adipocyte CAMK2 deficiency improves obesity-associated glucose intolerance.

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

Inhibition of CaM kinase II activation and force maintenance by KN-93 in arterial smooth muscle.

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：
0
作者：
A. Rokolya;H. Singer
通讯作者：
A. Rokolya;H. Singer

NADPH oxidase 4 is required for interleukin-1β-mediated activation of protein kinase Cδ and downstream activation of c-jun N-terminal kinase signaling in smooth muscle.

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。