The role of VSNL1 in human heart rate regulation
VSNL1在人体心率调节中的作用
基本信息
- 批准号:10750747
- 负责人:
- 金额:$ 8.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-30 至 2025-09-29
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAdrenergic AgentsAdrenergic AgonistsAdrenergic ReceptorAdrenergic beta-AntagonistsAffectAgonistArrhythmiaAtrial FunctionAttenuatedAutonomic nervous systemBiologicalBradycardiaCRISPR/Cas technologyCalciumCardiac conduction systemCardiovascular PhysiologyCardiovascular systemCell LineCell modelCell physiologyCellsCellular biologyCentral Nervous SystemCharacteristicsCholinergic AgonistsClinicalDataDerivation procedureDevelopmentElectrocardiogramElectrophysiology (science)EndocrineEtiologyExerciseGene Expression ProfilingGenerationsGenetic DatabasesGenetic EngineeringGenomicsGoalsHealthHeartHeart AtriumHeart RateHumanHuman ActivitiesIn VitroIndividualKnock-inKnock-outLeadLongevityMagnetic Resonance ImagingMapsMendelian randomizationMethodologyMethodsModelingMolecularMolecular ProfilingMorbidity - disease rateMuscle CellsNervous SystemNeurotransmitter ReceptorNeurotransmittersNodalOutcomePacemakersParticipantPatternPeriodicityPhenotypePhysiologicalPhysiologyPopulation GeneticsPrecision therapeuticsPrincipal InvestigatorProteinsProteomicsProtocols documentationRegulationReporterRestRoleSecondary toSignal PathwaySignal TransductionSinoatrial NodeStimulusStress TestsSystemTachycardiaTechnologyTestingTimeVSNL1 geneValidationVariantVentricularVentricular Functionbiobankcardiac magnetic resonance imagingcardiovascular effectscell typecholinergicclinical databaseclinical phenotypecohortdesigndifferentiation protocolembryonic stem cellepidemiology studygain of functiongenetic varianthuman datahuman embryonic stem cellhuman embryonic stem cell linein vitro Modelloss of functionmortalitynew therapeutic targetnodal myocytenull mutationparacrinepatch clampresponsesensorsingle-cell RNA sequencingstem cellstooltraffickingtranscriptomics
项目摘要
PROJECT SUMMARY
In the heart, pacemakers or sinoatrial node cells (SAN) initiate and maintain a rhythmic beating pattern that can
respond to external stimuli, including neurotransmitters, paracrine, and endocrine signals. In addition to its
clinical importance, resting heart rate is associated with lifespan across species, and has strong correlation with
longevity within individuals in several large epidemiologic studies. Despite their key role in human health and
physiology, the exact intracellular mechanism to maintain precise rhythmic oscillation is unknown, given the
limited access to these cells in the heart. The principal investigator hypothesizes that gene expression
analysis of the human sinoatrial node cell will identify cellular and physiologic features of human
pacemaking function. Recent technologies have enabled generating functional human SAN from embryonic
stem cells (hPSC-SAN) and performing molecular characterization at the single cell level. VSNL1, a calcium
sensing protein, was identified as a marker specific to SAN cells. I hypothesize that VSNL1 is uniquely
involved in heart rate regulation. Analyzing the genetic variants in VSNL1 gene and their effect on heart rate
in large biobanks will enable validation of the functional role of this protein in heart rate physiology. The applicant
will use large biobank cohorts and genetically engineered human embryonic stem cells to pursue the following
aims: First, determine the association between genetic variants in VSNL1 with cardiovascular physiology in
several large biobanks. Preliminary data in UK biobank (UKBB) cohort suggests significant association between
genetic variants in VSNL1 gene and baseline heart rate. The applicant will further study the effect of VSNL1
variants on heart rate with exercise, atrial and ventricular function (on cardiac MRI), and cardiovascular morbidity
and mortality outcomes in UKBB and other more diverse cohorts. Second, understand the effect of genetic
variants associated with heart rate in UKBB on molecular and electrophysiological characteristics of hPSC-SAN
cells in vitro. In preliminary data, the applicant has successfully confirmed the specific expression of VSNL1 in
hPSC-SAN cells and their absence in the human embryonic stem cells (hESC) derived ventricular myocytes.
Using CRISPR-Cas9 technology, the applicant has generated knock-out models of VSNL1 gene in hESC. The
applicant will use hESC lines carrying VSNL1 null mutation to generate hPSC-SAN lacking functional VSNL1.
Analyzing beating rate, calcium activity, and action potential using patch clamp will elucidate the cell type-specific
role of VSNL1 in human SAN biology. Third, perform functional studies to test the role of VSNL1 in hPSC-SAN
response to adrenergic and cholinergic signals. Recent studies support that VSNL1 is involved in
neurotransmitter receptor trafficking. The applicant will generate loss of function (LoF) and gain of function (GoF)
VSNL1 variants in hESC using the previously established protocols. The applicant will generate SAN cells from
hESCs carrying knock-out, GoF, or LoF VSNL1 variants to study the effect of various adrenergic and cholinergic
neurotransmitters on SAN cells’ beating rate, calcium, activity, and action potential.
项目总结
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 }}
ZANIAR GHAZIZADEH其他文献
ZANIAR GHAZIZADEH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 }}
相似海外基金
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
- 批准号:
8358448 - 财政年份:2012
- 资助金额:
$ 8.08万 - 项目类别:
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
- 批准号:
8517552 - 财政年份:2012
- 资助金额:
$ 8.08万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7952159 - 财政年份:2009
- 资助金额:
$ 8.08万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7952152 - 财政年份:2009
- 资助金额:
$ 8.08万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7719194 - 财政年份:2008
- 资助金额:
$ 8.08万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7605416 - 财政年份:2007
- 资助金额:
$ 8.08万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7605425 - 财政年份:2007
- 资助金额:
$ 8.08万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7378753 - 财政年份:2006
- 资助金额:
$ 8.08万 - 项目类别:
Adrenergic Agents for Methamphetamine: Outpatient Trials
甲基苯丙胺肾上腺素药物:门诊试验
- 批准号:
6825160 - 财政年份:2004
- 资助金额:
$ 8.08万 - 项目类别:
ADRENERGIC AGENTS FOR CARDIOPULMONARY RESUSCITATION
用于心肺复苏的肾上腺素能药物
- 批准号:
2702283 - 财政年份:1997
- 资助金额:
$ 8.08万 - 项目类别: