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:
- 金额:$ 31.49万
- 依托单位:
- 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:
- 关键词:
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.
项目总结:
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
A Role for Polo-Like Kinase 4 in Vascular Fibroblast Cell-Type Transition.
- DOI:10.1016/j.jacbts.2020.12.015
- 发表时间:2021-03
- 期刊:
- 影响因子:0
- 作者:Li J;Urabe G;Huang Y;Zhang M;Wang B;Marcho L;Shen H;Kent KC;Guo LW
- 通讯作者:Guo LW
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lianwang Guo其他文献
Lianwang Guo的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Lianwang Guo', 18)}}的其他基金
Master epigenetic regulators and retinal degenerative disease
掌握表观遗传调节因子和视网膜退行性疾病
- 批准号:
10306197 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Master epigenetic regulators and retinal degenerative disease
掌握表观遗传调节因子和视网膜退行性疾病
- 批准号:
10132335 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Master epigenetic regulators and retinal degenerative disease
掌握表观遗传调节因子和视网膜退行性疾病
- 批准号:
10376193 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Development of unimolecular nanoparticle-mediated periadventitial drug delivery system for sustained and targeted inhibition of intimal hyperplasia following open vascular reconstruction
开发单分子纳米粒子介导的外膜周围药物递送系统,用于持续和靶向抑制开放血管重建后的内膜增生
- 批准号:
10305283 - 财政年份:2020
- 资助金额:
$ 31.49万 - 项目类别:
Master epigenetic regulators and retinal degenerative disease
掌握表观遗传调节因子和视网膜退行性疾病
- 批准号:
9884774 - 财政年份:2019
- 资助金额:
$ 31.49万 - 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
- 批准号:
9513208 - 财政年份:2012
- 资助金额:
$ 31.49万 - 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
- 批准号:
8346582 - 财政年份:2012
- 资助金额:
$ 31.49万 - 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
- 批准号:
8700417 - 财政年份:2012
- 资助金额:
$ 31.49万 - 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
- 批准号:
8523895 - 财政年份:2012
- 资助金额:
$ 31.49万 - 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
- 批准号:
9117592 - 财政年份:2012
- 资助金额:
$ 31.49万 - 项目类别:
相似国自然基金
BET-Bromodomain小分子抑制剂和BET蛋白降解剂的设计合成及其表观遗传学性质研究
- 批准号:81673295
- 批准年份:2016
- 资助金额:59.0 万元
- 项目类别:面上项目
新型BET Bromodomain抑制剂治疗多发性硬化炎症反应的机制研究
- 批准号:81601409
- 批准年份:2016
- 资助金额:17.5 万元
- 项目类别:青年科学基金项目
基于片段的新型BET Bromodomain小分子抑制剂的设计、合成与生物活性研究
- 批准号:81473077
- 批准年份:2014
- 资助金额:70.0 万元
- 项目类别:面上项目
新型琥珀酰化、肉豆蔻酰化转移酶及其Bromodomain的发现
- 批准号:21302027
- 批准年份:2013
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
基于PCAF Bromodomain三维结构的抗艾滋病药物的设计与合成
- 批准号:30572234
- 批准年份:2005
- 资助金额:31.0 万元
- 项目类别:面上项目
酿酒酵母含Bromodomain转录因子Bdf1p在高盐胁迫反应中调控机制的研究
- 批准号:30570031
- 批准年份:2005
- 资助金额:26.0 万元
- 项目类别:面上项目
新bromodomain基因BRD7参与鼻咽癌细胞周期调控的机制研究
- 批准号:30400238
- 批准年份:2004
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
一个新的bromodomain基因的功能研究
- 批准号:30200135
- 批准年份:2002
- 资助金额:25.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Co-targeting BET Bromodomain Proteins and MNK Kinases in Pancreatic Cancer
胰腺癌中 BET 溴结构域蛋白和 MNK 激酶的共同靶向
- 批准号:
10338560 - 财政年份:2022
- 资助金额:
$ 31.49万 - 项目类别:
Co-targeting BET Bromodomain Proteins and MNK Kinases in Pancreatic Cancer
胰腺癌中 BET 溴结构域蛋白和 MNK 激酶的共同靶向
- 批准号:
10533366 - 财政年份:2022
- 资助金额:
$ 31.49万 - 项目类别:
Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML.
共同靶向 BET 溴结构域蛋白和 AML 中的异常信号传导。
- 批准号:
10454383 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Targeting epigenetic regulation via Bromodomain and Extraterminal (BET) domain inhibition for treatment of GVHD
通过 Bromodomain 和 Extraterminal (BET) 结构域抑制靶向表观遗传调控治疗 GVHD
- 批准号:
10383705 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Targeting epigenetic regulation via Bromodomain and Extraterminal (BET) domain inhibition for treatment of GVHD
通过 Bromodomain 和 Extraterminal (BET) 结构域抑制靶向表观遗传调控治疗 GVHD
- 批准号:
10602506 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML.
共同靶向 BET 溴结构域蛋白和 AML 中的异常信号传导。
- 批准号:
10302179 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Targeting epigenetic regulation via Bromodomain and Extraterminal (BET) domain inhibition for treatment of GVHD
通过 Bromodomain 和 Extraterminal (BET) 结构域抑制靶向表观遗传调控治疗 GVHD
- 批准号:
10211962 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML.
共同靶向 BET 溴结构域蛋白和 AML 中的异常信号传导。
- 批准号:
10674738 - 财政年份:2021
- 资助金额:
$ 31.49万 - 项目类别:
Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition
通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性
- 批准号:
10220910 - 财政年份:2020
- 资助金额:
$ 31.49万 - 项目类别:
Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition
通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性
- 批准号:
10026750 - 财政年份:2020
- 资助金额:
$ 31.49万 - 项目类别:














{{item.name}}会员




