Modulating BMPRII Signaling in Pulmonary Arterial Hypertension

调节肺动脉高压中的 BMPRII 信号传导

• 批准号: 8091016
• 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/8091016
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Project Narrative Our goal is to find ways to increase signaling through the receptor BMPRII by either modulating the levels of relevant micro-RNAs that impact BMPRII expression, or by screening for pharmacologically active compounds that could enhance signaling from the receptor. Using this approach, we hope to identify novel ways to prevent and treat pulmonary hypertension. !

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节BMPRII信号的途径。该信号通路与肺动脉高压（PAH）有关，该疾病是未经治疗的疾病，可直达心力衰竭和死亡。 70％的家族性患者和20％的特发性（I-）PAH患者在骨形态发生蛋白受体（BMPR）-II中携带突变。但是，开发PAH的渗透率小于20％。最近的研究表明，野生型BMPRII等位基因的水平降低了受影响和非影响家庭成员之间的区分。甚至与其他疾病相关的PAH（APAH）也可以伴随BMPRII的蛋白质表达降低。在某些IPAH患者中已经描述了BMPRII蛋白但不是mRNA的下调，这表明调节后的转录机制，对于许多没有突变的IPAH患者而言，这也可能是正确的。因此，一种新的方法可能最终导致预防和治疗肺动脉高压可能是BMPRII信号传导的恢复。微RNA参与基因表达的转录后调节，特别是microRNA 21（miR-21）可以靶向BMPRII mRNA。在特定目标1中，我们将使用miR-21模拟物和antagomirs来调节人肺动脉内皮细胞（PAEC）和平滑肌细胞（PASMC）以及从小鼠分离的小鼠中，BMPRII降低的细胞中，在人肺动脉内皮细胞（PAEC）和平滑肌细胞（PASMC）中调节miR-21和BMPRII的水平。此外，我们将通过增加BMPRII来恢复BMP信号传导和功能。具体目标2是通过筛选可以通过BMPRII增强信号传导的药理学活性化合物来追求第二个非常有前途的途径，以增加BMP信号传导。我们将使用3,600个FDA认可的药理学活性化合物来开发高吞吐量屏幕（HTS）。除了增强BMP信号传导的“命中”外，我们还将确定通过BMPRII受体抑制信号传导的分子，因此可能对IPAH患者和不受影响的BMPRII表达受损的家庭成员有害。我们将再次验证BMP信号传导和功能是否会增加BMP。这些结果为特定目标3奠定了基础，我们将首先使用MiR-21 Antagomirs以及在HTS中鉴定出的潜在“ BMP激活剂”，以增加体内的BMPRII信号传导。在BMPRII的杂合子中。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）的实验性PAH。我们的最终目标是使用具有最佳效率/副作用曲线的化合物进行临床试验。调节相关microRNA水平并确定可以通过恢复正常BMP信号来阻止pH值或反向pH的药物的机会是一个重大突破，这是一个重大突破。 公共卫生相关性：项目叙述我们的目标是通过调节影响BMPRII表达的相关微RNA的水平，或通过筛选可以增强受体信号传导的药理活性化合物来找到通过受体BMPRII增加信号传导的方法。使用这种方法，我们希望确定预防和治疗肺动脉高压的新颖方法。呢