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.

 DESCRIPTION (provided by application: There is a fundamental gap between our current treatment for Pulmonary Arterial Hypertension (PAH) with primary 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降低的BMPR2表达在血管细胞增殖中实现，并且该提案的总体目标是开发新的疗法，以逆转闭塞性的血管病，而新的途径会增加BMPR 2在PAH患者中均可降低BMPR 2的效果。可以在临床上使用障碍，从而确定可以用重新使用的药物来实现BMPR2修饰的基因，以提高BMPR2的表达，这是一种有望改善PAH，并具有清晰的热量转换路径，这是我们的三个重要部分。我们在siRNA高吞吐量筛选（HTS）中鉴定出的淋巴细胞特异性酪氨酸激酶（LCK），不仅在PAH功能上很重要，而且在PAH转录组数据库的荟萃分析中也高度表示，我们的强预序表现出了FHIT和LCK结果的不良表达。我们对人类PAH肺组织，内皮以及免疫力的研究表明，FHIT和LCK在PAH中被下调，并在pah中改变了疾病的渗透率，我们将在使用候选和umial re remize frightian frings Assay中，FHIT和LCK调节BMPR 2如何。人血管细胞和实验性肺动脉高压的异常表型，从而提供了一种清晰的治疗性转换途径，这是我们方法的三个创新方面。 （3）在药物上，我们将改革现有的药物，不仅可以节省时间和费用，而且可以加快其在监管机构的安全性和毒性信息中加快其在诊所的收养，因为我们拟议的研究的贡献非常重要，因为它利用新颖的途径来调节BMPR2基因的表达，而不是以前的链接，