Assessing the Impact of MSX1 in Cardiac Fibrosis and Sudden Cardiac Death
评估 MSX1 对心脏纤维化和心源性猝死的影响
基本信息
- 批准号:10241990
- 负责人:
- 金额:$ 5.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-17 至 2022-09-16
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectArrhythmiaBiological AssayBradyarrhythmiasCardiacCardiac MyocytesCardiac developmentCardiovascular systemCellsCessation of lifeChIP-seqClinicalComplexConnexin 43ConnexinsDataDiseaseDyesEchocardiographyEctopic Junctional TachycardiaElectrocardiogramElectrophysiology (science)Endothelial CellsEndotheliumEpithelialEventExhibitsFamilyFamily memberFibroblastsFibrosisFosteringGap JunctionsGenesGoalsHealthHeartHeart DiseasesHeart InjuriesHeart Valve DiseasesHeart failureHomeoboxHospitalizationImmunohistochemistryIn VitroIndividualInheritedKnock-outKnockout MiceLeadLeft ventricular non-compactionLuciferasesMSX1 geneMagnetic Resonance ImagingMedical GeneticsMedical HistoryMesenchymalMissionMolecularMorbidity - disease rateMusMuscleMutationMyocardial dysfunctionNational Heart, Lung, and Blood InstituteOutcomePathogenicityPathway interactionsPhenotypePhysiologicalPhysiologyProcessPublic HealthQuantitative Reverse Transcriptase PCRRNARegulationReportingRepressionResearchRoleTestingTherapeutic InterventionTranscription RepressorUnited StatesUnited States National Institutes of HealthWestern BlottingWorkaortic valve disorderchromatin immunoprecipitationcoronary fibrosisepithelial to mesenchymal transitionexome sequencinggene repressiongenetic testingheart functionhistological studiesimprovedinnovationinsightmortalitymouse modelnew therapeutic targetnovelpatch clampprematuresudden cardiac deathtranscription factortranscriptome sequencing
项目摘要
Project Summary
Heart failure (HF) remains a significant cause of morbidity and mortality in the United States; each year, 1
million deaths and 250,000 hospitalizations are directly attributed to HF. Cardiac fibrosis is a driver of heart
failure and valve disease. Clinically, cardiac fibrosis is a strong predictor of sudden cardiac death (SCD) in HF.
Both endothelial-to-mesenchymal transition (EndMT) or epithelial-to-mesenchymal transition (EMT) are able to
generate cardiac fibrosis in the adult heart which, in turn, predisposes individuals to HF, cardiac arrhythmias,
and SCD. While many pathways have been found to contribute to cardiac fibrosis, inherited mutations causing
fibrosis have not been readily identified.
We have identified a family with a complex medical history characterized by extensive cardiac fibrosis and
cardiac valve disease. We performed whole exome sequencing on affected members of this family and
identified a mutation in muscle segment homeobox 1 (MSX1-E135D) that was present in all members of the
family with disease. MSX1, also known as HOX7, is a transcription factor and a transcriptional repressor in the
heart. MSX1 participates in EndMT during cardiac development, but remains poorly studied in the adult heart.
The long-term objective of this application is to better understand the pathways and processes which underlie
inherited cardiac fibrosis. The specific objective of this project is to understand the role of MSX1 in the adult
heart and its contribution to cardiac fibrosis. We hypothesize that MSX1 regulates transcriptional repression of
gap junctions and EndMT in the adult heart, and that the loss of this regulation leads to cardiac fibrosis in
arrhythmias. We will test this hypothesis through two specific aims:
1) Define the physiologic role of Msx1 in the adult heart. We will characterize the effect of Msx1 cardiac-
specific deletion in the adult mouse heart by electrocardiography, echocardiography, cardiac MRI (cMRI),
invasive and non-invasive electrophysiology studies, and whole cell patch clamping of primary cardiomyocytes
of Msx1 cardiac-specific knockout and littermate control mice.
2) Define the molecular pathways by which Msx1 deletion causes cardiac dysfunction. We will test the function
of the MSX1-E135D mutation through luciferase assay of known genes repressed by MSX1. We will also test
for enhanced fibrosis in the hearts of our knockout mouse by immunohistochemistry for makers of fibroblasts
and endothelial cells. Also, we will use RNA- and ChIP-seq to define targets of Msx1 regulation in the heart.
When successful, these studies will implicate a new transcription factor in the development of cardiac fibrosis,
conduction disease, and HF. Further understanding of the function of MSX1 and its associated pathways in the
adult heart may lead to new targets for therapeutic intervention in cardiomyopathic and arrhythmogenic
conditions, supporting the Mission, Goals, and Objectives of the NHLBI.
项目摘要
心力衰竭(HF)仍然是美国发病率和死亡率的重要原因;每年,
一百万人死亡和25万人住院直接归因于心力衰竭。心脏纤维化是心脏的驱动力之一
衰竭和瓣膜疾病。临床上,心脏纤维化是心力衰竭患者心脏性猝死(SCD)的强烈预测因素。
内皮细胞到间质转化(EndMT)或上皮到间充质转化(EMT)都能够
在成人心脏中产生心脏纤维化,进而使个人容易患上心力衰竭、心律失常、
和SCD。虽然已发现许多途径导致心脏纤维化,但遗传突变导致
纤维化还不是很容易确定的。
我们已经确认了一个有复杂病史的家庭,其特征是广泛的心脏纤维化和
心脏瓣膜病。我们对这个家族中受影响的成员进行了完整的外显子组测序
发现了肌肉片段同源框1(Msx1-E135D)的突变,该突变存在于所有成员中
身患疾病的家庭。Msx1,也被称为HOX7,是一种转录因子,也是一种转录抑制因子。
心。Msx1参与心脏发育过程中的EndMT,但在成人心脏中的研究仍然很少。
此应用程序的长期目标是更好地理解其基础路径和过程
遗传性心脏纤维化。本项目的具体目标是了解Msx1在成人中的作用
心脏及其对心脏纤维化的贡献。我们假设Msx1调节转录抑制
在成人心脏中,缝隙连接和EndMT,并且这种调节的缺失导致心脏纤维化
心律不齐。我们将通过两个具体目标来检验这一假设:
1)明确Msx1在成人心脏中的生理作用。我们将描述Msx1对心脏的影响-
通过心电图、超声心动图、心脏磁共振成像(CMRI)、
原代心肌细胞的有创和无创电生理学研究及全细胞膜片钳
Msx1心脏特异性基因敲除小鼠和产仔对照小鼠。
2)明确Msx1缺失导致心功能不全的分子途径。我们将测试该功能
通过对Msx1抑制的已知基因进行荧光素酶分析,发现Msx1-E135D突变。我们还将测试
通过成纤维细胞标记物的免疫组织化学方法增强我们基因敲除小鼠心脏的纤维化
和内皮细胞。此外,我们还将使用RNA-和CHIP-SEQ来确定Msx1在心脏中的调控靶点。
如果成功,这些研究将表明一种新的转录因子与心脏纤维化的发展有关,
传导性疾病和心力衰竭。进一步了解Msx1及其相关信号通路在脑梗塞中的作用
成人心脏可能成为治疗心肌病和致心律失常的新靶点
条件,支持NHLBI的使命、目标和目的。
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)
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Alexander Greiner其他文献
Alexander Greiner的其他文献
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{{ truncateString('Alexander Greiner', 18)}}的其他基金
Assessing the Impact of MSX1 in Cardiac Fibrosis and Sudden Cardiac Death
评估 MSX1 对心脏纤维化和心源性猝死的影响
- 批准号:
9789034 - 财政年份:2018
- 资助金额:
$ 5.1万 - 项目类别:
Assessing the Impact of MSX1 in Cardiac Fibrosis and Sudden Cardiac Death
评估 MSX1 对心脏纤维化和心源性猝死的影响
- 批准号:
10005458 - 财政年份:2018
- 资助金额:
$ 5.1万 - 项目类别:
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