BET Bromodomain proteins as Novel Epigenetic Targets for prevention of Intimal Hyperplasia after Vascular Surgery

BET 溴结构域蛋白作为预防血管手术后内膜增生的新表观遗传靶点

基本信息

批准号：
10298010
负责人：
Lianwang Guo
金额：
$ 31.49万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10298010
关键词：
BET Bromodomain proteins Novel Epigenetic

项目摘要

Project Summary: Despite technological advances, arterial revascularization  especially peripheral angioplasty and bypass  often fail due to intimal hyperplasia (IH). The primary pathology of IH is the transformation of vascular smooth muscle cells (SMCs) from a quiescent state to an activated state, with multiple IH-promoting phenotypes. Currently, prevention of IH focuses on anti-proliferative agents with limited success. Moreover, a lack of insight exists into master proximal regulators that govern all of the major SMC pathogenic phenotypes, not only proliferation/migration, but also de-differentiation and inflammation. Identification and effective targeting of such master regulators would represent a major advance in anti-IH therapy. Recently, our team has identified that the bromo and extraterminal (BET) family of proteins, termed epigenetic readers, may uniquely fit this master role. Recent groundbreaking studies have revealed that the BET family of proteins can change the phenotype of different cell types, by coupling two acetyl-binding bromo-domains with acetylated key transcription factors consequently activating the transcription of a select subset of genes. We have made the exciting observation that the first-in-class BET inhibitor (JQ1) halts SMC pathogenic transformation and mitigates IH. This leads to our central hypothesis, that unlike downstream individual pathways that are subject to redundancy, BET proteins act as upstream drivers of nodal transcription factors (such as STAT3) which in turn determine downstream pathogenic SMC phenotypes. Since JQ1 globally blocks both bromo-domains in all three BET proteins, in this proposal we will differentiate the functions of the various BET proteins and bromo-domains in SMC transformation. In Aim1 we will determine which of the BET proteins dictate SMC pathogenic phenotypes and IH. We have observed that two BET proteins dramatically increase after arterial injury. In Aim2 we will further delineate which of the two bromo-domains is responsible for the BET pathogenic function. The rationale is based on our data that blocking the two bromo-domains (each in all three BET proteins) with respective inhibitors produces differential effects on SMC proliferation and inflammation. In Aim3 we will identify the key transcription factors that are governed by BET proteins, thereby mediating the BET function on SMC transformation. We have preliminarily identified STAT3 as a leading candidate. Our ultimate goal is to elucidate the specific BET protein or bromo-domain that is the most opportune target in the prevention of intimal hyperplasia. To this end, we will make use of the revolutionary CRISPR/Cas9 technology for BET protein knockout and bromo-domain mutation in the mouse genome. The proposal is novel because we will identify a key epigenetic switch that controls SMC pathogenic transformation. The research is significant because we will establish a BET protein or bromo-domain as a novel target for developing optimized therapeutic methods to treat IH and recurrent vascular disease.

项目摘要：尽管有技术进步，但动脉血运重建特别通常由于内膜增生（IH）而失败。 IH的主要病理是血管平滑的转化肌肉细胞（SMC）从静止状态到活化状态，具有多种促进IH的表型。目前，预防IH的重点是成功的抗增殖剂。而且，缺乏洞察力存在于管理所有主要SMC致病表型的主要近端调节剂中，不仅增殖/迁移，但也取消分化和炎症。识别和有效的目标主调节剂将代表抗IH疗法的重大进步。最近，我们的团队已经确定蛋白质的Bromo和外部（BET）家族称为表观遗传学读者，可能独特地适合该主人角色。最近的突破性研究表明，蛋白质的赌注家族可以改变表型不同的细胞类型，通过将两个乙酰结合Bromo膜与乙酰基键转录因子耦合因此会激活基因的精选子集的转录。我们做了令人兴奋的观察第一类BET抑制剂（JQ1）阻止了SMC致病性转化并减轻IH。这导致我们的核心假设，即与冗余的下游个体途径不同，押注蛋白质充当淋巴结转录因子的上游驱动因素（例如STAT3），从而决定下游致病SMC表型。由于JQ1在全球范围内都阻止了这两个BET中的两个Bromo域蛋白质，在此提案中，我们将区分各种BET蛋白质和Bromo蛋白的功能 SMC转换。在AIM1中，我们将确定哪种BET蛋白决定SMC致病表型和IH。我们已经观察到，动脉损伤后两种BET蛋白质急剧增加。在AIM2中，我们将进一步描述了两个Bromo域中的哪一个负责BET致病功能。理由是基于我们的数据，该数据旨在阻止两个Bromo域（每个BET蛋白中的每个）在AIM3中，我们将确定钥匙由BET蛋白控制的转录因子，从而介导SMC的BET功能转型。我们已将STAT3定为主要候选人。我们的最终目标是阐明特定的BET蛋白或Bromo域，这是预防内膜的最机会目标增生。为此，我们将利用革命性的CRISPR/CAS9技术用于BET蛋白小鼠基因组中的敲除和溴核突变。该提议是新颖的，因为我们将确定控制SMC致病转化的关键表观遗传开关。这项研究很重要，因为我们将建立BET蛋白或Bromo域作为开发优化的治疗方法的新靶标治疗IH和复发性血管疾病。