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Genotype-guided therapy for atrial fibrillation

Genotype-guided therapy for atrial fibrillation
心房颤动的基因型引导治疗
批准号:
10215617
负责人:
Dawood Darbar
金额:
$69.34万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-15 至 2025-06-30

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中文摘要
翻译
房颤(AF)是一种日益流行的疾病,到2050年,约有1600万美国人受到影响。尽管最近 以导管为基础的治疗进展,抗心律失常药物(AADS)仍被广泛用于治疗 症状性房颤。然而,单个患者的反应是高度可变的,并可能与 严重的毒性。AADS在治疗房颤方面的有限成功部分是由于 潜在的底物和我们无法预测个体对治疗的反应。因此,一个重大的知识差距 正在预测哪些房颤患者可能对抗心律失常治疗有反应。新出现的证据 支持这里要检验的最重要的假设,即对AADS的反应的变异性是由一个 与房颤相关的单核苷酸多态性(SNP)。尽管房颤的遗传方法揭示了 对治疗的敏感性和反应受底层底物的调节,这些底物的翻译 对患者床边护理的发现一直受到限制,部分原因是对 风险等位基因引起房颤的潜在机制,与确定治疗相关的挑战 有效性和缺乏前瞻性的基因指导研究。目标1将检验这样的假设:一个常见的 染色体(CHR)4q25 AF SNP利用LOAD调节症状性房颤患者对AADS的反应 作为治疗效果的衡量标准。这项建议的科学前提是基于我们已发表的研究 这表明,chr4q25 SNP不仅可以预测房颤症状的成功控制,而且 携带风险等位基因的人对钠通道的反应比钾通道阻滞剂AADS更好;最近的一项研究表明 证实了我们的临床观察;以及在我们的试点和可行性研究中产生的初步数据。我们建议 一项随机交叉研究,患者将服用氟卡胺/索他洛尔,治疗效果将是 通过植入可插入式心脏监测器进行评估。虽然我们发现携带chr4q25的房颤患者 房颤风险等位基因比携带野生型(WT)等位基因的人更有可能对氟卡胺产生反应, 对AADS的这种不同反应的潜在机制尚不清楚。目标2将阐明 Chr4q25风险SNP差异性调节对AADS反应的潜在细胞机制 房颤患者使用人心房多能干细胞来源的心肌细胞(hiPSC-CMS)。第一, 我们将从chr4q25风险携带者和WT等位基因携带者中产生心房IpSC-CMS。第二,我们将检验这一假设 可以提高心房IPSC-CMS的电生理功能和结构成熟度。 体内相关细胞-细胞、细胞-细胞外基质和细胞可溶性因子的微环境工程 互动。第三,我们将确定成熟的心房IPSC-CMS的EP表型与chr4q25房颤风险和 WT等位基因携带者,并检测氟卡胺和索他洛尔的体外效应。拟议的研究不仅将 改善房颤患者对AADS反应的预测,为基因引导的方法铺平道路 也方便了个性化医疗的实践。
英文摘要
Atrial fibrillation (AF) is a growing epidemic with ~16 million Americans affected by 2050. Despite recent advances in catheter-based therapy, antiarrhythmic drugs (AADs) are still commonly used to treat patients with symptomatic AF. However, response in an individual patient is highly variable and can be associated with significant toxicities. The limited success of AADs in treating AF is due in part to heterogeneity of the underlying substrate and our inability to predict individual responses to therapy. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to antiarrhythmic therapy. Emerging evidence supports the overarching hypothesis to be tested here that variability in response to AADs is modulated by a single nucleotide polymorphism (SNP) associated with AF. Although genetic approaches to AF have revealed that susceptibility to and response to therapy is modulated by the underlying substrate, the translation of these discoveries to the bedside care of patients has been limited in part because of poor understanding of the underlying mechanisms by which risk alleles cause AF, challenges associated with determining the therapeutic efficacy and lack of prospective genotype-guided studies. Aim 1 will test the hypothesis that a common chromosome (chr) 4q25 AF SNP modulates response to AADs in patients with symptomatic AF using burden as a measure of therapeutic efficacy. The scientific premise for this proposal is based on our published study which showed that a chr4q25 SNP not only predicted successful symptom control of AF but that patients who carried the risk allele responded better to Na+-channel than K+-channel blocker AADs; a recent study that confirmed our clinical observation; and preliminary data generated in our pilot and feasibility study. We propose a randomized cross-over study whereby patients will be given flecainide/sotalol and therapeutic efficacy will be assessed by implanting insertable cardiac monitors. While we showed that AF patients who carry the chr4q25 AF risk allele are more likely to respond to flecainide than those who carry the wild-type (WT) allele, the underlying mechanism for this differential response to AADs is poorly understood. Aim 2 will elucidate the underlying cellular mechanisms by which a chr4q25 risk SNP differentially modulates response to AADs in patients with AF using human atrial induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). First, we will generate atrial iPSC-CMs from chr4q25 risk and WT allele carriers. Second, we will test the hypothesis that the electrophysiologic (EP) and structural maturity of atrial iPSC-CMs can be enhanced by precise microenvironmental engineering of in-vivo relevant cell-cell, cell-extracellular matrix, and cell-soluble factor interactions. Third, we will determine the EP phenotypes of mature atrial iPSC-CMs from chr4q25 AF risk and WT allele carriers and examine the effects of flecainide and sotalol ex-vivo. The proposed studies will not only improve the prediction of response to AADs for AF patients and pave the way for a genotype-guided approach but also facilitate the practice of personalized medicine.
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Genotype-guided therapy for atrial fibrillation
Genotype-guided therapy for atrial fibrillation
Human iPSC-derived atrial cardiomyocytes to model atrial fibrillation in a dish
Human iPSC-derived atrial cardiomyocytes to model atrial fibrillation in a dish
国内基金
海外基金
具有抗癌活性的天然产物金霉酸(Aureolic acids)全合成与选择性构建2-脱氧糖苷键
  • 批准号:
    22007039
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    24.0万元
  • 批准年份:
    2020
  • 负责人:
    王黎明
  • 依托单位:
海洋放线菌来源聚酮类化合物Pteridic acids生物合成机制研究
手性Lewis Acids催化的分子内串联1,5-氢迁移/环合反应及其在构建结构多样性手性含氮杂环化合物中的应用
对空气稳定的新型的有机金属Lewis Acids催化剂制备、表征与应用研究
  • 批准号:
    21172061
  • 项目类别:
    面上项目
  • 资助金额:
    30.0万元
  • 批准年份:
    2011
  • 负责人:
    许新华
  • 依托单位: