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
• 负责人: Edda Frauke Spiekerkoetter
• 金额: $ 43.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923720
• 关键词: Adenoviruses; Adoption; Animal Model; Apoptosis; Biological Assay; Blood Vessels; Cell Proliferation; Cells; Cessation of life; Chemosensitization; Clinic; Clinical; DNA Damage; Dasatinib; Data; Data Set; Databases; Development; Disease; Dose; Endothelium; Enhancers; Epigenetic Process; FDA approved; FHIT gene; FK506; Face; Fibroblasts; Gene Expression; Genes; Genetic Transcription; Goals; Heart failure; Histopathology; Human; Hypoxia; Immune; Impairment; Left; Link; Lung; Lung Transplantation; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Messenger RNA; Meta-Analysis; MicroRNAs; Mission; Modeling; National Heart, Lung, and Blood Institute; Nude Rats; Pathogenesis; Pathology; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Phenotype; Proliferating; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Rattus; Regulation; Research; Rodent; Safety; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Speed; Structure of parenchyma of lung; Therapeutic; Time; Toxic effect; Translating; Translations; Tube; Vascular Diseases; Vasodilator Agents; Work; base; bone morphogenetic protein receptors; cell type; clinical practice; cost; high risk; high throughput screening; improved; innovation; mRNA Expression; new therapeutic target; novel; novel therapeutics; overexpression; prevent; public health relevance; pulmonary arterial hypertension; pulmonary artery endothelial cell; pulmonary function; receptor; transcription factor; transcriptomics

 DESCRIPTION (provided by applicant: There is a fundamental gap between our current treatment for Pulmonary Arterial Hypertension (PAH) with primarily vasodilators, and the need to reverse the occlusive vasculopathy of pulmonary arteries that results in increased pulmonary vascular resistance and right heart failure. Increasingly, Bone Morphogenetic Protein Receptor 2 (BMPR2) signaling is recognized as a key pathway and potential master switch in PAH with reduced BMPR2 expression implicated in vascular cell proliferation and occlusive vasculopathy. The overall goal of this proposal thus is to develop new therapies to reverse the occlusive vasculopathy by novel pathways that increase BMPR2 expression. The mechanism by which BMPR2 is downregulated in PAH patients is not known. Strategies to increase BMPR2 signaling have shown promise in experimental pulmonary hypertension yet most approaches still face many obstacles before they can be used clinically. Thus, identifying BMPR2 modifier genes that could be harnessed with repurposed drugs to increase BMPR2 expression would be a promising strategy to improve PAH with a clear path to therapeutic translation. Our proposal has three significant parts, which are represented by our three specific aims: First, we will focus on novel BMPR2 modifier genes, Fragile Histidine Triad (FHIT) and Lymphocyte specific protein tyrosine Kinase (LCK) that we identified in an siRNA High Throughput Screen (HTS) and that are not only functionally important in PAH but also highly represented in a meta-analysis of PAH transcriptomic databases. Our strong preliminary data showed that decreased expression of FHIT and LCK resulted in reduced BMPR2 mRNA expression and impaired function of pulmonary vascular cells. Our studies on human PAH lung tissue, endothelial as well as immune cells suggested that FHIT and LCK are downregulated in PAH and modify disease penetrance in familial PAH. Second, we will determine how FHIT and LCK regulate BMPR2 on the epigenetic and transcriptional level using candidate and unbiased profiling assay approaches. Third, we will determine whether a drug that increases FHIT, Enzastaurin, reverses the abnormal phenotype of human vascular cells and experimental pulmonary hypertension, thus offering a clear path to a therapeutic translation. Three innovative aspects underlie our approach: (1) conceptually, we will target BMPR2 expression by modulating two novel genes that have not been describe in PAH before (2) technically, we used a novel siRNA high Throughput Screen that has not been used to identify BMPR2 modifier genes in PAH and (3) pharmacologically, we will repurpose existing drugs which not only saves time and expense but can speed their adoption in the clinic because of known safety and toxicity information from regulatory agencies. The contribution of our proposed research is highly significant to the field o PAH, as it utilizes novel pathways to regulate BMPR2 gene expression by repurposing drugs not previously linked to either the receptor or to PAH.

 描述（由申请人提供：我们目前主要使用血管扩张剂治疗肺动脉高压（PAH），与逆转导致肺血管阻力增加和右心衰竭的肺动脉闭塞性血管病变的需要之间存在根本差距。 , 骨形态发生蛋白受体 2 (BMPR2) 信号传导被认为是 PAH 中 BMPR2 表达减少的关键途径和潜在的主开关因此，该提案的总体目标是开发新的疗法，通过增加 BMPR2 表达的新途径来逆转闭塞性血管病变。 BMPR2 在 PAH 患者中下调的机制尚不清楚。增加 BMPR2 信号传导已在实验性肺动脉高压中显示出希望，但大多数方法在临床使用之前仍面临许多障碍，因此，鉴定可利用的 BMPR2 修饰基因。重新利用药物来增加 BMPR2 表达将是改善 PAH 的一种有前途的策略，并具有明确的治疗转化途径。我们的建议包括三个重要部分，这由我们的三个具体目标代表：首先，我们将重点关注新型 BMPR2 修饰基因 Fragile。我们在 siRNA 高通量筛选 (HTS) 中鉴定出组氨酸三联体 (FHIT) 和淋巴细胞特异性蛋白酪氨酸激酶 (LCK)，它们不仅在 PAH 中具有重要的功能，而且高度我们对 PAH 转录组数据库的荟萃分析显示，FHIT 和 LCK 表达减少导致 BMPR2 mRNA 表达减少，并损害了肺血管细胞的功能。细胞表明 FHIT 和 LCK 在 PAH 中下调，并改变家族性 PAH 的疾病外显率 其次，我们将使用 FHIT 和 LCK 如何在表观遗传和转录水平上调节 BMPR2。第三，我们将确定增加 FHIT 的药物 Enzastaurin 是否可以逆转人类血管细胞和实验性肺动脉高压的异常表型，从而为治疗转化提供一条明确的途径。我们的方法的三个创新方面。 ：（1）从概念上讲，我们将通过调节两个以前未在 PAH 中描述过的新基因来靶向 BMPR2 表达（2）从技术上讲，我们使用了一种尚未用于鉴定的新型 siRNA 高通量筛选PAH 中的 BMPR2 修饰基因和（3）药理学上，我们将重新利用现有药物，这不仅节省时间和费用，而且由于监管机构已知的安全性和毒性信息，可以加快其在临床中的采用。我们提出的研究的贡献是巨大的。它对 PAH 领域具有重要意义，因为它通过重新利用以前与受体或 PAH 无关的药物，利用新的途径来调节 BMPR2 基因表达。