BMP2 Gene Regulation in Calcific Aortic Valve Disease
BMP2 基因在钙化主动脉瓣疾病中的调控
基本信息
- 批准号:8852685
- 负责人:
- 金额:$ 38.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-23 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAdultAnimal ModelAreaBMP2 geneBacterial Artificial ChromosomesBindingBiological MarkersBiologyCalcifiedCellsCellular biologyCholesterolChromosome MappingCis TestsCollectionConsensusConserved SequenceDNA SequenceDefectDevelopmentDiagnosisDiagnosticDietDiseaseDisease ProgressionDisease modelEarly DiagnosisElectrophoretic Mobility Shift AssayElementsEnhancersFGF2 geneFishesFutureGene Expression RegulationGenesGeneticGenetic PolymorphismGenetic TranscriptionGoalsIndividualKnockout MiceKnowledgeLifeMammalsMapsMedicalMicroRNAsModelingMolecularMorphogenesisMusMutateOperative Surgical ProceduresOsteoblastsOsteogenesisPatternPredispositionProteinsRNARNA SequencesReagentRegulationRegulatory ElementReporterReporter GenesResearchResearch InfrastructureShapesSignal PathwaySignal TransductionSiteStagingSurveysTestingTherapeuticTherapeutic InterventionTranscriptTransfectionabstractingaortic valveaortic valve disorderbicuspid aortic valvebonebone morphogenetic protein 2calcificationchromatin immunoprecipitationfeedinggene repressiongenetic elementimprovedinterestinterstitial cellmalformationmouse modelnew therapeutic targetnotch proteinnovel strategiesosteoblast differentiationosteogenicpreventrecombinaseresponsetherapeutic targettranscription factortranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant):
Congenital valve defects promote Calcific Aortic Valve Disease (CAVD). Bone morphogenetic protein 2 (BMP2) is a key signal in valve development. In diseased adult valves, the pro-calcific BMP2 and downstream responses stimulate calcification. Thus, aberrant BMP2 patterns and levels influence CAVD indirectly by disrupting valve shape and directly by inducing ectopic bone formation. Our overall hypothesis is that controlling BMP2 levels would be an effective medical therapy for CAVD. Our strategy is to elucidate how BMP2 levels are controlled in the aortic valve during normal valve development and under conditions that promote CAVD. Aim 1. To test DNA sequences that control BMP2 synthesis at the transcriptional level in the valves of mice that model CAVD and during valve development. This aim will use an existing collection of reagents and mice that were created to survey bone regulatory sequences. One region includes a conserved bone enhancer that binds the master bone differentiation transcription factor RUNX2 and other potential regulators. We will test ECR1 and map other cis-elements that control Bmp2 expression in mice that develop CAVD when fed a high cholesterol diet and during the early stages of normal aortic valve development. Aim 2. To test RNA sequences that control BMP2 synthesis at the post-transcriptional level in developing valves and in the valves of mice that model CAVD. Both positive and negative mechanisms influence BMP2 synthesis in the aortic valve. A sequence conserved between mammals and fishes strongly represses BMP2 reporter gene repression in the developing and adult aortic valve. We will test the hypothesis that this element and its flanking RNA prevent BMP2 synthesis and ectopic bone in aortic valves in the Notch-compromised CAVD model. We will also test this regulatory mechanism during normal aortic valve development. Aim 3. To identify trans-regulatory molecules that control Bmp2 transcription through ECR1. The trans-regulatory factors that bind ECR1 may promote BMP2 synthesis in calcifying aortic valves. Molecular studies will be used to define factors interacting with the ECR1 sequence. The association of RUNX2 and Hes1 will be examined in MC3T3-E1 pre-osteoblasts that express BMP2 in response to FGF2. These findings will be confirmed in primary aortic valve interstitial cells and diseased valves from the CAVD mouse model. Aim 4. To identify trans-regulatory molecules that control BMP2 synthesis at the post- transcriptional level. We will test the influence of microRNAs that target the BMP2 transcript MC3T3-E1 cells and primary valve interstitial cells. This study will provide fundamental knowledge regarding the spatial and temporal control of Bmp2 in a new model of CAVD and in the developing aortic valve. These studies will direct future tests of anti-BMP2 therapies in CAVD. This proposal explores these Specific Areas of Research Interest: Genetics of CAVD and bicuspid aortic valve, Infrastructure (improved animal models), Cell biology (signaling pathways, mechanisms, and regulation of calcification), and Diagnosis.
(End of Abstract)
描述(由申请人提供):
先天性瓣膜缺陷促进钙化性主动脉瓣疾病(CAVD)。骨形态发生蛋白2(BMP 2)是瓣膜发育的关键信号。在患病的成人瓣膜中,促钙化BMP 2和下游反应刺激钙化。因此,异常的BMP 2模式和水平通过破坏瓣膜形状间接影响CAVD,并通过诱导异位骨形成直接影响CAVD。我们的总体假设是,控制BMP 2水平将是CAVD的有效药物治疗。我们的策略是阐明在正常瓣膜发育过程中和促进CAVD的条件下,BMP 2水平是如何在主动脉瓣中控制的。目标1.检测在CAVD模型小鼠瓣膜和瓣膜发育过程中在转录水平控制BMP 2合成的DNA序列。这一目标将使用现有的试剂和小鼠的集合,这些试剂和小鼠是为了调查骨调控序列而创建的。一个区域包括保守的骨增强子,其结合主骨分化转录因子RUNX 2和其他潜在的调节因子。我们将测试ECR 1和映射其他顺式元件,控制Bmp 2表达的小鼠,发展CAVD时,喂养高胆固醇饮食和正常主动脉瓣发育的早期阶段。目标2.检测在发育瓣膜和CAVD模型小鼠瓣膜中在转录后水平控制BMP 2合成的RNA序列。积极和消极的机制都影响主动脉瓣中BMP 2的合成。哺乳动物和鱼类之间的保守序列强烈抑制BMP 2报告基因在发育和成年主动脉瓣中的抑制。我们将检验这一假设,即该元件及其侧翼RNA在Notch受损的CAVD模型中阻止BMP 2合成和主动脉瓣异位骨。我们还将在正常主动脉瓣发育过程中检测这种调节机制。目标3.鉴定通过ECR 1控制Bmp 2转录的反式调节分子。结合ECR 1的反式调节因子可能促进钙化主动脉瓣中BMP 2的合成。分子研究将用于确定与ECR 1序列相互作用的因子。RUNX 2和Hes 1的关联将在MC 3 T3-E1前成骨细胞中检查,所述前成骨细胞响应于FGF 2表达BMP 2。这些发现将在CAVD小鼠模型的原发性主动脉瓣间质细胞和病变瓣膜中得到证实。目标4。鉴定在转录后水平控制BMP 2合成的反式调节分子。我们将测试靶向BMP 2转录MC 3 T3-E1细胞和原代瓣膜间质细胞的microRNA的影响。这项研究将提供有关Bmp 2在CAVD新模型和发育中的主动脉瓣中的空间和时间控制的基础知识。这些研究将指导CAVD中抗BMP 2疗法的未来测试。该提案探讨了这些特定的研究领域:CAVD和二叶式主动脉瓣的遗传学,基础设施(改进的动物模型),细胞生物学(信号通路,机制和钙化调节)和诊断。
(End摘要)
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MicroRNA Profiles in Calcified and Healthy Aorta Differ: Therapeutic Impact of miR-145 and miR-378.
钙化主动脉和健康主动脉中的 MicroRNA 谱存在差异:miR-145 和 miR-378 的治疗影响。
- DOI:10.1152/physiolgenomics.00074.2020
- 发表时间:2020
- 期刊:
- 影响因子:4.6
- 作者:Tang,Ying;Shah,TapanA;Yurkow,EdwardJ;Rogers,MelissaB
- 通讯作者:Rogers,MelissaB
Turning Bone Morphogenetic Protein 2 (BMP2) on and off in Mesenchymal Cells.
- DOI:10.1002/jcb.25164
- 发表时间:2015-10
- 期刊:
- 影响因子:4
- 作者:Rogers MB;Shah TA;Shaikh NN
- 通讯作者:Shaikh NN
Genetic background influences the impact of KLOTHO deficiency.
遗传背景影响 KLOTHO 缺陷的影响。
- DOI:10.1152/physiolgenomics.00094.2020
- 发表时间:2020
- 期刊:
- 影响因子:4.6
- 作者:Salloum,JawadS;Garsetti,DianeE;Rogers,MelissaB
- 通讯作者:Rogers,MelissaB
Characterization of new bone morphogenetic protein (Bmp)-2 regulatory alleles.
- DOI:10.1002/dvg.23035
- 发表时间:2017-07
- 期刊:
- 影响因子:0
- 作者:Shah TA;Zhu Y;Shaikh NN;Harris MA;Harris SE;Rogers MB
- 通讯作者:Rogers MB
Dynamics and cellular localization of Bmp2, Bmp4, and Noggin transcription in the postnatal mouse skeleton.
- DOI:10.1002/jbmr.2313
- 发表时间:2015-01
- 期刊:
- 影响因子:0
- 作者:Pregizer SK;Mortlock DP
- 通讯作者:Mortlock DP
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DOUGLAS P MORTLOCK其他文献
DOUGLAS P MORTLOCK的其他文献
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{{ truncateString('DOUGLAS P MORTLOCK', 18)}}的其他基金
BMP2 Gene Regulation in Calcific Aortic Valve Disease
BMP2 基因在钙化主动脉瓣疾病中的调控
- 批准号:
8535814 - 财政年份:2012
- 资助金额:
$ 38.41万 - 项目类别:
BMP2 Gene Regulation in Calcific Aortic Valve Disease
BMP2 基因在钙化主动脉瓣疾病中的调控
- 批准号:
8353323 - 财政年份:2012
- 资助金额:
$ 38.41万 - 项目类别:
BMP2 Gene Regulation in Calcific Aortic Valve Disease
BMP2 基因在钙化主动脉瓣疾病中的调控
- 批准号:
8697127 - 财政年份:2012
- 资助金额:
$ 38.41万 - 项目类别:
"Gdf6 gene expression and evolution in vertebrates"
“Gdf6 基因在脊椎动物中的表达和进化”
- 批准号:
7929967 - 财政年份:2009
- 资助金额:
$ 38.41万 - 项目类别:
A Conserved Sequence Approach for MS Association Studies
MS 关联研究的保守序列方法
- 批准号:
7036281 - 财政年份:2006
- 资助金额:
$ 38.41万 - 项目类别:
A Conserved Sequence Approach for MS Association Studies
MS 关联研究的保守序列方法
- 批准号:
7160493 - 财政年份:2006
- 资助金额:
$ 38.41万 - 项目类别:
Gdf6 gene expression and evolution in vertebrates
Gdf6 基因在脊椎动物中的表达和进化
- 批准号:
6829973 - 财政年份:2005
- 资助金额:
$ 38.41万 - 项目类别:
"Gdf6 gene expression and evolution in vertebrates"
“Gdf6 基因在脊椎动物中的表达和进化”
- 批准号:
7555081 - 财政年份:2005
- 资助金额:
$ 38.41万 - 项目类别:
"Gdf6 gene expression and evolution in vertebrates"
“Gdf6 基因在脊椎动物中的表达和进化”
- 批准号:
7105193 - 财政年份:2005
- 资助金额:
$ 38.41万 - 项目类别:
"Gdf6 gene expression and evolution in vertebrates"
“Gdf6 基因在脊椎动物中的表达和进化”
- 批准号:
7342122 - 财政年份:2005
- 资助金额:
$ 38.41万 - 项目类别:
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