Identification of a novel modulator of Pulmonary Artery Hypertension

一种新型肺动脉高压调节剂的鉴定

基本信息

批准号：
9282758
负责人：
Akiko Hata
金额：
$ 63.09万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282758
关键词：
Actins Adult Affect Alleles Animal Model BMPR2 gene Cessation of life Chemosensitization Chronic Development Disease Embryo Etiology Exhibits Exons FMR1 Genes Genetic Germ-Line Mutation Heart failure Heritability Hypoxia Intervention LIM Domain Kinase 1 LIMK1 gene Left Length Leucine Lung Medial Mediating Messenger RNA Mutation Nucleotides Pathogenesis Patients Penetrance Protein-Serine-Threonine Kinases Proteins Pulmonary Vascular Resistance Pulmonary artery structure RNA-Binding Proteins Rattus Rodent Model Role Signal Pathway Signal Transduction Signal Transduction Pathway Smooth Muscle Myocytes Sprague-Dawley Rats Stimulus Testing Transcript Translational Regulation Translations Vascular remodeling Ventricular bone morphogenetic protein receptor type II extracellular genome editing high risk mouse model mutant novel novel therapeutics overexpression premature prognostic tool protein expression public health relevance pulmonary arterial hypertension rat genome response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Pulmonary Artery Hypertension (PAH) is a disease of the pulmonary vasculature characterized by progressive remodeling of pulmonary arteries (PAs), including proliferation of PA smooth muscle cells (PASMC). PAH is an incurable disease that leads to death from right ventricular heart failure in less than 3 years if untreated. Heterozygous mutations of the bone morphogenetic protein type II receptor (BMPR2) gene are the most common genetic cause of heritable PAH (HPAH). However, only 20% of BMPR2 carriers actually develop PAH, indicating an existence of additional factors or modifier genes that trigger the development of PAH in a small subset of BMPR2 carriers. Therefore, it is critical to develop a prognostic tool to identify the subset of BMPR2 carriers who will develop PAH. The discovery of a BMPR2 modulating factor can also help clarify the etiology of HPAH, identify potential therapeutic targets, and develop a novel therapeutic strategy for HPAH. We found recently that the region of the BMPR2 mRNA mediates the translational regulation of BMPR2 by the RNA binding protein FMRP (fragile X mental retardation protein), a product of the FMR1 gene. Overexpression of FMRP reduces BMPR2 protein, while deletion of FMRP in PASMC results in a ~3-fold increase of both BMPR2 expression and of its downstream signal response, including actin remodeling mediated by LIM-kinase 1 (LIMK1), which interacts with the CTD. The central hypothesis of this application is that FMRP is a regulator of BMPR2 protein level and its downstream CTD- mediated signaling pathway, and, therefore, serves as a critical modifier of PAH among BMPR2 carriers. In Specific Aim1 will test the hypothesis that the depletion of FMRP will ameliorate PAH by augmenting BMPR2 protein and its downstream signaling pathway. Specific Aim2 will test the hypothesis that the change of the level of FMPR modulates the translation efficiency of BMPR2-FL transcripts and contributes to the pathogenesis of PAH. Specific Aim3 will test the hypothesis that the elevated expression of FMRP affects the penetrance of PAH. Upon successfully completion of the application, it will identify a previously unappreciated "modifier" which triggers the development of PAH among a small subset of BMPR2 carriers.

描述（由申请人提供）：肺动脉高血压（PAH）是一种肺血管疾病，其特征是肺动脉（PA）进行性重塑，包括PA平滑肌细胞（PASMC）的增殖，是一种导致无法治愈的疾病。如果不治疗，不到 3 年内死于右心室心力衰竭的人数最多的是骨形态发生蛋白 II 型受体 (BMPR2) 基因的杂合突变。然而，只有 20% 的 BMPR2 携带者实际上会发生 PAH，这表明在一小部分遗传携带者中存在触发 PAH 发生的其他因素或修饰基因。开发一种预后工具来识别将发生 PAH 的 BMPR2 携带者子集。BMPR2 调节因子的发现还可以帮助阐明 HPAH 的病因，确定潜在的治疗靶点，我们最近发现 BMPR2 mRNA 区域通过 RNA 结合蛋白 FMRP（脆性 X 智力迟钝蛋白）介导 BMPR2 的翻译调节，FMRP 是 FMRP BMPR2 过度表达的产物。蛋白，而 PASMC 中 FMRP 的缺失导致 BMPR2 表达及其下游信号反应增加约 3 倍，包括由LIM 激酶 1 (LIMK1)，与 CTD 相互作用该应用的中心假设是 FMRP 是 BMPR2 蛋白水平及其下游 CTD 介导的信号通路的调节剂，因此，作为 PAH 的关键调节剂。在 Specific Aim1 中，BMPR2 携带者将测试 FMRP 的缺失将通过增强 BMPR2 蛋白及其下游信号通路来改善 PAH 的假设。成功完成后，将测试 FMPR 水平的变化调节 BMPR2-FL 转录物的翻译效率并有助于 PAH 发病机制的假设。在该应用程序中，它将识别出一个以前未被重视的“修饰符”，该修饰符会在一小部分 BMPR2 携带者中触发 PAH 的发展。