Modulating BMPRII Signaling in Pulmonary Arterial Hypertension

调节肺动脉高压中的 BMPRII 信号传导

• 批准号: 8703752
• 负责人: Edda Frauke Spiekerkoetter
• 金额: $ 12.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8703752
• 关键词: 7-(N-(3-aminopropyl)amino)heptan-2-one; Adverse effects; Affect; Alleles; Apoptosis; Biological Assay; Cell Line; Cells; Cessation of life; Clinical Trials; Disease; Down-Regulation; FDA approved; Family member; Gene Expression Regulation; Goals; Heart failure; Human; Hypoxia; Immigration; Individual; Lead; Libraries; Link; Luciferases; Lung; MAPK14 gene; Messenger RNA; Methods; MicroRNAs; Mus; Mutation; Myoblastoma; Patients; Penetrance; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Prevention; Prevention approach; Proteins; Pulmonary Hypertension; Receptor Signaling; Regulation; Resistance; Response Elements; STAT3 gene; Serotonin; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Staging; Stimulus; Testing; Tube; United States National Institutes of Health; abstracting; bone morphogenetic protein receptor type II; drinking water; high throughput screening; improved; in vivo; inhibitor/antagonist; novel strategies; platelet-derived growth factor BB; prevent; promoter; protein expression; pulmonary arterial hypertension; pulmonary artery endothelial cell; receptor; response; restoration; screening; small molecule

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：我的建议的主要目标是发现调节BMPRII信号的途径。这种信号通路与肺动脉高压（PAH）相关，PAH是一种如果不治疗会导致右心衰竭和死亡的疾病。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，PAH的发生率低于20%。最近的研究表明，野生型BMPRII等位基因水平的降低区分了受影响和未受影响的家庭成员。甚至与其他疾病相关的PAH（APAH）也可伴有BMPRII蛋白表达降低。在一些IPAH患者中已经描述了BMPRII蛋白而不是mRNA的下调，这表明了转录后调节机制，并且对于许多没有突变的IPAH患者也可能是如此。因此，一种可能最终导致肺动脉高压预防和治疗的新方法可能是恢复BMPRII信号传导。微小RNA参与基因表达的转录后调节，并且微小RNA 21（miR-21）特别地可以靶向BMPRII mRNA。在具体目标1中，我们将使用miR-21模拟物和miR-21抑制剂来调节人肺动脉内皮细胞（PAECS）和平滑肌细胞（PASMC）以及从BMPRII水平降低的小鼠分离的细胞中miR-21和BMPRII的水平。此外，我们将证实，BMP信号和功能的BMP响应增加BMPRII恢复。具体目标2是寻求第二个非常有前途的途径，以增加BMP信号，通过筛选可增强通过BMPRII的信号传导的生物活性化合物。我们将使用3，600种FDA批准的生物活性化合物开发高通量筛选（HTS）。除了增强BMP信号传导的“命中”之外，我们还将鉴定抑制通过BMPRII受体的信号传导的分子，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信号传导和响应BMP的功能将增加。这些结果为特异性目标3奠定了基础，在该目标中，我们将首先使用miR-21 miR-21和HTS中鉴定的潜在“BMP激活剂”来增加体内BMPRII信号传导，即。在BMPRII杂合子小鼠中。其次，我们将证明上述方法将预防或逆转BMPRII杂合小鼠（用缺氧和5-羟色胺刺激）中的实验性PAH。我们的最终目标是启动一项临床试验，该化合物具有最佳的效果/副作用。有机会调节相关microRNA的水平，并确定FDA批准的药物，可以通过恢复正常的BMP信号传导来阻止进展或逆转PH，这将是一个重大突破。