Modulating BMPRII Signaling in Pulmonary Arterial Hypertension
调节肺动脉高压中的 BMPRII 信号传导
基本信息
- 批准号:8703752
- 负责人:
- 金额:$ 12.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:7-(N-(3-aminopropyl)amino)heptan-2-oneAdverse effectsAffectAllelesApoptosisBiological AssayCell LineCellsCessation of lifeClinical TrialsDiseaseDown-RegulationFDA approvedFamily memberGene Expression RegulationGoalsHeart failureHumanHypoxiaImmigrationIndividualLeadLibrariesLinkLuciferasesLungMAPK14 geneMessenger RNAMethodsMicroRNAsMusMutationMyoblastomaPatientsPenetrancePharmaceutical PreparationsPharmacologic SubstancePhosphorylationPreventionPrevention approachProteinsPulmonary HypertensionReceptor SignalingRegulationResistanceResponse ElementsSTAT3 geneSerotoninSignal PathwaySignal TransductionSmooth Muscle MyocytesStagingStimulusTestingTubeUnited States National Institutes of Healthabstractingbone morphogenetic protein receptor type IIdrinking waterhigh throughput screeningimprovedin vivoinhibitor/antagonistnovel strategiesplatelet-derived growth factor BBpreventpromoterprotein expressionpulmonary arterial hypertensionpulmonary artery endothelial cellreceptorresponserestorationscreeningsmall molecule
项目摘要
DESCRIPTION (provided by applicant): Project summary/ Abstract: The main goal of my proposal is uncover avenues that modulate BMPRII signaling. This signaling pathway is relevant in pulmonary arterial hypertension (PAH), a disease leading if untreated, to right heart failure and death. 70% of patients with familial and 20% of patients with idiopathic (I-) PAH carry a mutation in the bone morphogenetic protein receptor (BMPR)-II. However, the penetrance to develop PAH is less than 20%. Recent studies have shown that reduced levels of the wild-type BMPRII allele discriminate between affected and non- affected family members. Even PAH associated with other diseases (APAH) can be accompanied by reduced protein expression of BMPRII. Downregulation of BMPRII protein, but not mRNA, has been described in some IPAH patients, suggesting a post-transcriptional mechanism of regulation and this may also be true for the many IPAH patients without mutations. Therefore a novel approach that might ultimately lead to the prevention and treatment of pulmonary hypertension could be restoration of BMPRII signaling. Micro RNAs are involved in posttranscriptional regulation of gene expression, and microRNA 21 (miR-21) in particular can target BMPRII mRNA. In Specific Aim 1 we will use miR-21 mimics and antagomirs to modulate the levels of miR-21 and BMPRII in human pulmonary artery endothelial cells (PAECS) and smooth muscle cells (PASMCs) as well as in cells isolated from a mouse with reduced BMPRII levels. In addition we will confirm that BMP signaling and function in response to BMPs are restored by increasing BMPRII. Specific Aim 2 is to pursue a second very promising avenue to increase BMP signaling by screening for pharmacologically active compounds that could enhance signaling via BMPRII. We will develop a High Throughput Screen (HTS) using 3,600 FDA approved pharmacologically active compounds. In addition to "hits" that enhance BMP signaling, we will identify molecules that inhibit signaling through the BMPRII receptor and could therefore be harmful in IPAH patients and non-affected family members with compromised BMPRII expression. We will again verify that BMP signaling and function in response to BMP will be increased. These results set the stage for Specific Aim 3, where we will first use miR-21 antagomirs as well as a potential "BMP activator" identified in the HTS to increase BMPRII signaling in vivo, ie. in mice heterozygous for BMPRII. Second we will show that the above approach will prevent or reverse experimental PAH in BMPRII heterozygous mice (stimulated with hypoxia and Serotonin). Our ultimate goal is to initiate a clinical trial with the compound with the best efect/side-effect profile. The opportunity to modulate levels of relevant microRNAs and to identify a FDA approved drug that could arrest the progression or reverse PH by restoring normal BMP signaling would be a major breakthrough.
描述(由申请人提供):项目摘要/摘要:我的提案的主要目标是发现调制BMPRII信号的途径。这种信号通路与肺动脉高压(PAH)有关,如果不治疗,肺动脉高压会导致右心衰和死亡。70%的家族性PAH患者和20%的特发性(I-) PAH患者携带骨形态发生蛋白受体(BMPR)- ii突变。然而,发生PAH的外显率不到20%。最近的研究表明,野生型BMPRII等位基因水平的降低在受影响和未受影响的家庭成员之间存在差异。即使是与其他疾病相关的PAH (APAH)也可能伴有BMPRII蛋白表达的降低。在一些IPAH患者中,BMPRII蛋白下调,但mRNA不下调,这提示了一种转录后调节机制,这可能也适用于许多没有突变的IPAH患者。因此,一种可能最终导致预防和治疗肺动脉高压的新方法是恢复BMPRII信号。微rna参与基因表达的转录后调控,尤其是microRNA 21 (miR-21)可以靶向BMPRII mRNA。在特异性目标1中,我们将使用miR-21模拟物和拮抗剂来调节人肺动脉内皮细胞(PAECS)和平滑肌细胞(PASMCs)以及从BMPRII水平降低的小鼠分离的细胞中的miR-21和BMPRII水平。此外,我们将证实BMP信号传导和BMP响应功能通过增加BMPRII得以恢复。具体目标2是寻求第二种非常有希望的途径,通过筛选可以通过BMPRII增强信号传导的药理活性化合物来增加BMP信号传导。我们将使用3600种FDA批准的药理活性化合物开发高通量筛选(HTS)。除了增强BMP信号传导的“击中”外,我们还将鉴定通过BMPRII受体抑制信号传导的分子,因此可能对IPAH患者和BMPRII表达受损的未受影响的家庭成员有害。我们将再次验证BMP信号和响应BMP的功能将增加。这些结果为特异性目标3奠定了基础,我们将首先使用miR-21拮抗剂以及在HTS中发现的潜在的“BMP激活剂”来增加体内BMPRII信号。在小鼠中杂合BMPRII。其次,我们将证明上述方法可以预防或逆转BMPRII杂合小鼠(缺氧和血清素刺激)的实验性PAH。我们的最终目标是启动具有最佳效果/副作用的化合物的临床试验。有机会调节相关microrna的水平,并确定一种FDA批准的药物,可以通过恢复正常的BMP信号来阻止进展或逆转PH值,这将是一个重大突破。
项目成果
期刊论文数量(0)
专著数量(0)
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Edda Frauke Spiekerkoetter其他文献
Edda Frauke Spiekerkoetter的其他文献
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{{ truncateString('Edda Frauke Spiekerkoetter', 18)}}的其他基金
Understanding and targeting molecular and cellular events responsible for pulmonary arteriovenous malformation development, growth and regression
了解和靶向导致肺动静脉畸形发生、生长和消退的分子和细胞事件
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10718086 - 财政年份:2023
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Understanding and targeting molecular as well as structural events governing right ventricular adaptation, failure and recovery in pulmonary hypertension using repurposed drugs
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10615148 - 财政年份:2021
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$ 12.12万 - 项目类别:
Understanding and targeting molecular as well as structural events governing right ventricular adaptation, failure and recovery in pulmonary hypertension using repurposed drugs
使用重新利用的药物了解和靶向控制肺动脉高压右心室适应、衰竭和恢复的分子和结构事件
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10456651 - 财政年份:2021
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$ 12.12万 - 项目类别:
Understanding and targeting molecular as well as structural events governing right ventricular adaptation, failure and recovery in pulmonary hypertension using repurposed drugs
使用重新利用的药物了解和靶向控制肺动脉高压右心室适应、衰竭和恢复的分子和结构事件
- 批准号:
10278668 - 财政年份:2021
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Targeting Novel BMPR2 modifiers in Pulmonary Hypertension with Repurposed Drugs
用新用途药物靶向治疗肺动脉高压的新型 BMPR2 修饰剂
- 批准号:
9923720 - 财政年份:2016
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Modulating BMPRII Signaling in Pulmonary Arterial Hypertension
调节肺动脉高压中的 BMPRII 信号传导
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8890864 - 财政年份:2011
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$ 12.12万 - 项目类别:
Modulating BMPRII Signaling in Pulmonary Arterial Hypertension
调节肺动脉高压中的 BMPRII 信号传导
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8308378 - 财政年份:2011
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$ 12.12万 - 项目类别:
Modulating BMPRII Signaling in Pulmonary Arterial Hypertension
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8520385 - 财政年份:2011
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$ 12.12万 - 项目类别:
Modulating BMPRII Signaling in Pulmonary Arterial Hypertension
调节肺动脉高压中的 BMPRII 信号传导
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8091016 - 财政年份:2011
- 资助金额:
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