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）相关，肺动脉高压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 的外显率低于 20%。最近的研究表明，野生型 BMPRII 等位基因水平的降低可以区分受影响和未受影响的家庭成员。即使与其他疾病相关的 PAH (APAH) 也可能伴有 BMPRII 蛋白表达的降低。在一些 IPAH 患者中已经描述了 BMPRII 蛋白而非 mRNA 的下调，这表明转录后调节机制，这对于许多没有突变的 IPAH 患者来说也可能是正确的。因此，恢复 BMPRII 信号传导可能是最终预防和治疗肺动脉高压的一种新方法。 Micro 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。在具体目标 1 中，我们将使用 miR-21 模拟物和 antagomir 来调节人肺动脉内皮细胞 (PAECS) 和平滑肌细胞 (PASMC) 以及从小鼠分离的细胞中 miR-21 和 BMPRII 的水平BMPRII 水平。此外，我们将确认通过增加 BMPRII 可以恢复 BMP 信号传导和响应 BMP 的功能。具体目标 2 是通过筛选可通过 BMPRII 增强信号传导的药理活性化合物，寻求第二种非常有前途的途径来增加 BMP 信号传导。我们将使用 3,600 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“命中”之外，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。我们将再次验证增加BMP信令和响应BMP的功能。这些结果为具体目标 3 奠定了基础，我们将首先使用 miR-21 antagomir 以及 HTS 中鉴定的潜在“BMP 激活剂”来增加体内 BMPRII 信号传导，即。 BMPRII 杂合小鼠。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。调节相关 microRNA 水平并确定 FDA 批准的药物的机会将是一个重大突破，该药物可以通过恢复正常的 BMP 信号来阻止进展或逆转 PH。