Phosphorylation and gating of cardiac connexin channels
心脏连接蛋白通道的磷酸化和门控
基本信息
- 批准号:9078759
- 负责人:
- 金额:$ 39.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2020-01-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcuteAddressAdultAffinityAlanineAnti-Arrhythmia AgentsArrhythmiaAspartateBackBehaviorBerylliumBlood flowCardiacCardiac MyocytesCellsCessation of lifeCommunicationConnexin 43ConnexinsCouplingCyclic AMP-Dependent Protein KinasesDataDevelopmentDiseaseEventFailureGlobal ChangeGoalsHeartHeart AtriumHeart DiseasesHeterogeneityImplantable DefibrillatorsInjuryIntercalated discKnowledgeLeadLigandsLinkMediatingMethodsModelingMolecularMuscle CellsOutputPathway interactionsPatternPeriodicityPermeabilityPhosphorylationPhysiologicalPropertyProtein DephosphorylationProteinsPublishingRattusRegulationSignal TransductionSiteStagingStructureTachycardiaTestingTherapeutic UsesTissuesUncertaintyVentricularVentricular FibrillationVentricular Tachycardiabasecalmodulin-dependent protein kinase IIcoronary artery occlusiondesigngap junction channelheart functionimprovedinjuredinsightinsulinomaintercellular communicationmeetingsmutantnovel therapeuticsparticlepeptidomimeticspreconditioningpreventpublic health relevancereceptorsudden cardiac deathtargeted treatmenttherapy designtoolvoltagevoltage clamp
项目摘要
DESCRIPTION (provided by applicant): Gap junction channels (GJCh) comprise the pathway for intercellular propagation of the electrical signals responsible for coordinated activation of cardiac contraction; heterogeneity and failure of GJCh function lead to heterogeneous slowing of conduction and consequent micro- or macro-reentry circuits that set the stage for tachycardia and fibrillation in the atria and ventricles. Heterogeneity and failure of GJCh function reflect acute, phosphorylation-dependent regulation of GJCh gating and conductance. This application focuses on the GJCh gating and conductance changes that are antiarrhythmic (preconditioning) and proarrhythmic, contributing to sudden cardiac death. The long-term goals of the project are to: 1) understand the mechanisms underlying phosphorylation-dependent regulation of Cx43 GJCh and hemichannel (HCh) function, and 2) develop from that knowledge peptidomimetics that will target or induce specific functional properties of Cx43 channels that will preserve cardiac rhythmicity and prevent irreversible injury. Two key issues limit our ability to implement Cx43 based therapies. First, we do not understand the consequences of differential Cx43 phosphorylation on GJCh function. Second, the impact of heterogeneous Cx43 phosphorylation on impulse propagation in the heart is unknown. Because these issues cannot be addressed in pairs of adult ventricular myocytes (due to heterogeneity of Cx43 phosphorylation state and the large number of functioning GJChs that preclude study of gating and single channel behavior by the necessary whole-cell voltage clamp methods), we address our aims using site-mutants of Cx43 that mimic the phosphorylation state of Cx43 in normally functioning, preconditioned and injured heart. We express these Cx43 site mutants in Cx-deficient rat insulinoma cells, Cx43-deficient cardiomyocytes, and wild-type cardiomyocytes, where their gating, conductance and antiarrhythmic properties can be studied. The results of our studies will guide design and testing of function- specific, high-affinity peptidomimetics to interfere with or mimic the interactions tht underlie anti-arrhythmic GJCh and HCh function. The proposed combination of molecular, structural and functional approaches can be expected to provide new mechanistic insight on regulation of the dynamic function of Cx43 GJChs as they support the extraordinary dynamic range of cardiac function. In addition, we expect to develop Cx43- and function-specific, experimentally and therapeutically useful tools that will protect coordinated function of the heart
despite ongoing disease and pharmacologic therapies.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JANIS M BURT其他文献
JANIS M BURT的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JANIS M BURT', 18)}}的其他基金
Role of Connexin47 mutations in primary lymphedema
Connexin47 突变在原发性淋巴水肿中的作用
- 批准号:
8831729 - 财政年份:2014
- 资助金额:
$ 39.57万 - 项目类别:
Role of Connexin47 mutations in primary lymphedema
Connexin47 突变在原发性淋巴水肿中的作用
- 批准号:
8677486 - 财政年份:2014
- 资助金额:
$ 39.57万 - 项目类别:
GAP JUNCTIONS IN VASCULAR SMOOTH MUSCLE--GROWTH CONTROL
血管平滑肌的间隙连接——生长控制
- 批准号:
6030845 - 财政年份:1997
- 资助金额:
$ 39.57万 - 项目类别:
Gap Junctions in Vascular Smooth Muscle: Growth Control
血管平滑肌的间隙连接:生长控制
- 批准号:
8209153 - 财政年份:1997
- 资助金额:
$ 39.57万 - 项目类别:
Gap junctions in Vascular Smooth Muscle: growth control
血管平滑肌的间隙连接:生长控制
- 批准号:
7039119 - 财政年份:1997
- 资助金额:
$ 39.57万 - 项目类别:
Gap junctions in Vascular Smooth Muscle: growth control
血管平滑肌的间隙连接:生长控制
- 批准号:
6929542 - 财政年份:1997
- 资助金额:
$ 39.57万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 39.57万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 39.57万 - 项目类别:
Operating Grants