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:9789034
- 负责人:
- 金额:$ 2.97万
- 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 JunctionsGenesGenetic screening methodGoalsHealthHeartHeart 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 Repressor/CorepressorUnited StatesUnited States National Institutes of HealthWestern BlottingWorkaortic valve disorderchromatin immunoprecipitationcoronary fibrosisepithelial to mesenchymal transitionexome sequencinggene repressionheart 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,1
100万例死亡和250,000例住院治疗直接归因于HF。心脏纤维化是心脏的驱动力
衰竭和瓣膜疾病。临床上,心脏纤维化是HF患者心源性猝死(SCD)的强预测因子。
内皮-间充质转化(EndMT)或上皮-间充质转化(EMT)都能够
在成人心脏中产生心脏纤维化,这反过来使个体易于发生HF,心律失常,
和SCD。虽然已经发现许多途径有助于心脏纤维化,但遗传性突变导致心脏纤维化。
纤维化还不容易鉴别。
我们发现了一个具有复杂病史的家族,其特征是广泛的心脏纤维化,
心脏瓣膜病我们对这个家族中受影响的成员进行了全外显子组测序,
发现了一个肌肉节段同源异型框1(MSX 1-E135 D)突变,该突变存在于所有成员中。
家人有病。MSX 1,也称为HOX 7,是一种转录因子和转录抑制因子,在细胞内表达。
心MSX 1在心脏发育过程中参与EndMT,但在成人心脏中的研究仍然很少。
这项应用的长期目标是更好地了解其背后的途径和过程,
遗传性心脏纤维化该项目的具体目标是了解MSX 1在成人中的作用。
心脏及其对心脏纤维化的贡献。我们假设MSX 1调节转录抑制,
成年人心脏中的缝隙连接和EndMT,这种调节的丧失导致心脏纤维化,
心律不齐我们将通过两个具体目标来检验这一假设:
1)确定Msx 1在成人心脏中的生理作用。我们将描述Msx 1心脏的作用-
通过心电图、超声心动图、心脏MRI(cMRI),
侵入性和非侵入性电生理学研究,以及原代心肌细胞的全细胞膜片钳
Msx 1心脏特异性基因敲除小鼠和同窝对照小鼠。
2)确定Msx 1缺失导致心功能障碍的分子途径。我们将测试函数
通过对MSX 1抑制的已知基因的荧光素酶测定来检测MSX 1-E135 D突变。我们还将测试
通过免疫组织化学检测成纤维细胞标记物,
和内皮细胞。此外,我们将使用RNA和ChIP-seq来定义心脏中Msx 1调节的靶点。
一旦成功,这些研究将暗示一种新的转录因子参与心脏纤维化的发展,
传导疾病和HF。进一步了解MSX 1的功能及其相关通路,
成人心脏可能会导致新的目标,为治疗干预心肌病和心血管疾病
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:
10241990 - 财政年份:2018
- 资助金额:
$ 2.97万 - 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:
$ 2.97万 - 项目类别:
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