Aortic Valve Disease: Mechanisms and Therapeutic Approaches

主动脉瓣疾病:机制和治疗方法

基本信息

  • 批准号:
    10548842
  • 负责人:
  • 金额:
    $ 67.91万
  • 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:
    2020-02-10 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Aortic valve stenosis is the major cause of valve disease in the Western world, and the third leading cause of adult heart disease. It is a progressive disorder that worsens with age. Thickening of the aortic valve is followed by calcification that results in further stenosis that ultimately necessitates surgical replacement. A major risk factor for calcific aortic valve disease (CAVD) is bicuspid aortic valve (BAV), which is present in 1–2% of the population, and involves formation of a two- rather than three-valve leaflet. ~35% of individuals with BAV will develop CAVD with age, but some with BAV have thickening even in childhood, requiring intervention. There are no medical treatments available for CAVD patients, and the only clinical option is surgical valve replacement. We reported that heterozygous nonsense mutations in the NOTCH1 (N1) transcription factor cause congenital biscuspid aortic valve (BAV) and severe CAVD and evidence suggests N1 is haploinsufficient in valve endothelial cells (ECs). Induced pluripotent stem cell (iPSC)-derived ECs from several patients with CAVD and N1 haploinsufficiency showed increased expression of pro-osteogenic and inflammatory signaling. Network analysis revealed key nodes that were responsible for much of the gene dysregulation. A chemical screen for the ability to restore expression of 120 dysregulated genes by targeted RNA-sequencing revealed several drugs that restored the network close to the N1+/+ state in human iPSC-ECs, with one, XCT790, showing efficacy in vivo for aortic valve thickening, calcification and stenosis in a mouse model. XCT790 is annotated to function as an inhibitor of estrogen-related receptor alpha (ERRα). We now propose to test the hypotheses that XCT790 prevents aortic valve disease by inhibiting ERRα activity, can treat established disease, and can function in a subset of CAVD patient cells without N1 mutations. The aims are 1) to determine the mechanism of action by which XCT790 corrects disease-associated gene expression and prevents aortic valve disease; 2) to determine if XCT790 can treat established CAVD or prevent neonatal valve stenosis; and 3) to determine if gene dysregulation in primary aortic valve endothelial cells from sporadic CAVD patients with or without genetic variants in NOTCH1 pathway genes is responsive to XCT790. These studies will advance a potential therapeutic to treat a disease that represents an enormous unmet medical need, is characterized by high mortality and morbidity, and for which the only current remedy is a highly invasive surgery.
主动脉瓣狭窄是西方世界瓣膜疾病的主要原因,也是成人心脏病的第三大原因。这是一种随年龄增长而逐渐加重的疾病。主动脉瓣增厚后会发生钙化,导致进一步狭窄,最终需要手术置换。钙化性主动脉瓣疾病(CAVD)的一个主要风险因素是二叶式主动脉瓣(BAV),其存在于1-2%的人群中,并且涉及两瓣而不是三瓣叶的形成。约35%的BAV患者会随着年龄的增长而发展为CAVD,但一些BAV患者甚至在儿童时期就已经增厚,需要干预。CAVD患者没有可用的药物治疗,唯一的临床选择是外科瓣膜置换术。我们报告了NOTCH 1(N1)转录因子的杂合无义突变导致先天性双瓣主动脉瓣(BAV)和严重的CAVD,并且有证据表明N1在瓣膜内皮细胞(EC)中单倍不足。诱导多能干细胞(iPSC)衍生的EC从几个CAVD和N1单倍不足的患者表现出增加的表达的促成骨和炎症信号。网络分析揭示了导致大部分基因失调的关键节点。通过靶向RNA测序恢复120个失调基因表达的能力的化学筛选揭示了几种药物,这些药物在人类iPSC-EC中恢复了接近N1+/+状态的网络,其中一种是XCT 790,在小鼠模型中显示出对主动脉瓣增厚,钙化和狭窄的体内疗效。XCT 790被注释为雌激素相关受体α(ERRα)的抑制剂。我们现在建议检验以下假设:XCT 790通过抑制ERRα活性预防主动脉瓣疾病,可以治疗已确定的疾病,并且可以在无N1突变的CAVD患者细胞亚群中发挥作用。目的是:1)确定XCT 790纠正疾病相关基因表达和预防主动脉瓣疾病的作用机制; 2)确定XCT 790是否可以治疗已建立的CAVD或预防新生儿瓣膜狭窄;和3)确定来自散发性CAVD患者的原发性主动脉瓣内皮细胞中的基因失调是否对NOTCH 1途径基因的遗传变异有反应,XCT 790。这些研究将推进一种潜在的治疗方法,以治疗代表巨大未满足的医疗需求的疾病,其特征在于高死亡率和发病率,并且目前唯一的治疗方法是高度侵入性手术。

项目成果

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DEEPAK SRIVASTAVA其他文献

DEEPAK SRIVASTAVA的其他文献

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{{ truncateString('DEEPAK SRIVASTAVA', 18)}}的其他基金

Small molecule therapeutic for calcific aortic valve disease
钙化性主动脉瓣疾病的小分子治疗
  • 批准号:
    10735711
  • 财政年份:
    2023
  • 资助金额:
    $ 67.91万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10471982
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10245025
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
  • 批准号:
    10471980
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
  • 批准号:
    10245029
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
  • 批准号:
    10006031
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10006184
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
  • 批准号:
    10471988
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
  • 批准号:
    10245023
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
  • 批准号:
    10006188
  • 财政年份:
    2019
  • 资助金额:
    $ 67.91万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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