Elucidating the Molecular Mechanisms and Cellular Specificity of HDAC Inhibitor Efficacy in Diastolic Dysfunction

阐明 HDAC 抑制剂治疗舒张功能障碍的分子机制和细胞特异性

• 批准号: 10664222
• 负责人: Joshua Travers
• 金额: $ 10.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664222
• 关键词: ATAC-seq; Ablation; Animals; Architecture; Attenuated; Award; Binding Proteins; Bioinformatics; Biology; Cardiac; Cardiovascular Diseases; Cells; Characteristics; Chromatin; Clinical; Colorado; Complement; Complex; Core Facility; Data; Deposition; Development; Dose Limiting; EFRAC; Environment; Enzymes; Epigenetic Process; Extracellular Matrix; Family; Fibroblasts; Flow Cytometry; Foundations; Functional disorder; Future; Galectin 1; Genes; Genetic; Genetic Transcription; Genomics; Goals; HDAC1 gene; Heart; Heart failure; Hematology; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Impairment; Inflammatory; Inflammatory Response; Infrastructure; Injury; Institution; International; Knowledge; Laboratories; Left; Macrophage; Mediating; Medical; Mentors; Mentorship; Molecular; Mus; Myofibroblast; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Polysaccharides; Population; Process; Prognosis; Property; Protein Isoforms; Proteomics; Relaxation; Research; Research Personnel; Resolution; Risk; Role; Signal Transduction; Small Interfering RNA; Solid; Specificity; Syndrome; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Training; Treatment Efficacy; Universities; Ventricular; biobank; cardioprotection; cell type; clinically relevant; coronary fibrosis; epigenetic regulation; epigenomics; genetic corepressor; genome-wide; inflammatory modulation; inhibitor; innovation; knock-down; mortality; mouse model; next generation sequencing; novel; novel therapeutic intervention; patient population; pharmacologic; pre-clinical; preservation; pressure; recruit; single-cell RNA sequencing; skill acquisition; small molecule inhibitor; standard of care; success; transcriptome sequencing; transcriptomics; treatment strategy

PROJECT SUMMARY Diastolic dysfunction (DD), characterized by impaired left ventricular compliance and relaxation, is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF), a devastating syndrome with poor prognosis for which there currently exist limited therapeutic interventions. Dynamic acetylation of histones represents a critical component of chromatin-dependent signal transduction involved in the activation of cardiac fibroblasts (CFs) and increased extracellular matrix deposition, leading to progressive DD and development of HFpEF. These processes are largely regulated by histone deacetylases (HDACs), a family of epigenetic regulatory enzymes whose pharmacological inhibition is cardioprotective in the setting of DD; however, little is known regarding the HDAC isoform specificity and molecular mechanisms mediating this protection. This Pathway to Independence award will leverage innovative small molecule inhibitors, genetics- based strategies for cell type-specific gene ablation, and the integration of multifaceted state-of-the-art epigenomic and bioinformatics techniques to examine the cell type- and isoform-specificity of HDAC inhibition (Aims 1 and 2), and therapeutic potential of inhibition of a novel glycan binding protein (Aim 3), in myofibroblast activation, cardiac fibrosis and DD. In Aims 1 and 2, the applicant will train with co-mentors and advisors in the K99 phase in a single-cell, genome-wide next generation sequencing technology that characterizes chromatin architecture, a flow cytometry-based technique for characterizing inflammatory cells, an integrated approach to transcriptomics and proteomics analyses in primary human CFs, and a genetics-based approach for cell type- specific gene ablation, all with the overall goal of defining the cellular specificity and molecular mechanisms mediating the cardioprotective properties of HDAC inhibition. In the R00 phase described in Aim 3, the applicant will utilize the skills acquired in the K99 phase to investigate the role and therapeutic potential of inhibiting the glycan-binding protein Galectin-1, recently discovered to be significantly altered in the CF population of mice with DD and subjected to HDAC inhibition, in myofibroblast activation, cardiac remodeling, and the progression to HFpEF. The applicant possesses extensive prior knowledge in epigenetics, CF biology, and the pathophysiology of DD and fibrotic remodeling. Furthermore, the mentorship team consists of internationally recognized leaders in epigenetic regulation of cardiovascular disease, clinical HFpEF, murine models of HF, and emerging bioinformatics technologies. The environment at the University of Colorado Anschutz Medical Campus is exemplary for collaborative and innovative research, with an excellent infrastructure including a human heart biorepository and outstanding core facilities. In summary, the exceptional mentoring team and institutional environment will provide a solid foundation for the applicant’s development into an independent investigator. Moreover, this innovative approach offers the exciting potential to contribute to the development of desperately needed novel therapeutic strategies for the treatment of heart failure.

项目摘要 舒张功能障碍（DD），其特征是左心室顺应性和舒张功能受损， 发生射血分数保留性心力衰竭（HFpEF）的风险增加， 其预后差，目前存在有限的治疗干预。动态乙酰化 组蛋白是染色质依赖性信号转导的关键成分，参与了细胞的活化， 心脏成纤维细胞（CF）和细胞外基质沉积增加，导致进行性DD和 HFpEF的发展。这些过程在很大程度上受组蛋白脱乙酰酶（HDAC）的调节，HDAC是一个组蛋白脱乙酰酶家族。 表观遗传调节酶，其药理学抑制作用在DD背景下具有心脏保护作用; 然而，关于HDAC同种型特异性和介导这一过程的分子机制知之甚少 保护这个独立之路奖将利用创新的小分子抑制剂，遗传学- 基于细胞类型特异性基因消融的策略，以及多方面最先进技术的整合 表观基因组学和生物信息学技术，以检查HDAC抑制的细胞类型和亚型特异性 (Aims 1和2），以及在肌成纤维细胞中抑制新型聚糖结合蛋白（Aim 3）的治疗潜力 激活、心脏纤维化和DD。在目标1和2中，申请人将在以下方面与共同导师和顾问进行培训： 在表征染色质的单细胞、全基因组下一代测序技术中的K99期 结构，一种基于流式细胞术的技术，用于表征炎症细胞，一种整合的方法， 转录组学和蛋白质组学分析，以及基于遗传学的细胞类型分析方法， 特异性基因消融，所有这些的总体目标都是定义细胞特异性和分子机制 介导HDAC抑制的心脏保护特性。在目标3所述的R 00阶段，申请人 将利用在K99阶段获得的技能来研究抑制肿瘤生长的作用和治疗潜力。 聚糖结合蛋白Galectin-1，最近发现在CF小鼠群体中显著改变 与DD和HDAC抑制，在肌成纤维细胞活化，心脏重塑，和进展， 到HFpEF。申请人在表观遗传学、CF生物学和遗传学方面具有广泛的先验知识。 DD的病理生理学和纤维化重塑。此外，导师团队由国际人士组成 在心血管疾病、临床HFpEF、HF小鼠模型的表观遗传调控方面公认的领导者， 新兴的生物信息技术。科罗拉多大学安舒茨医学院的环境 是合作和创新研究的典范，拥有包括人类心脏在内的优秀基础设施 生物储存库和出色的核心设施。总而言之，出色的辅导团队和机构 环境将为申请人发展成为独立调查员提供坚实的基础。 此外，这种创新的方法提供了令人兴奋的潜力，有助于发展拼命 需要新的治疗策略来治疗心力衰竭。

项目成果

Substrate stiffness modulates cardiac fibroblast activation, senescence, and proinflammatory secretory phenotype.

基质硬度调节心脏成纤维细胞活化、衰老和促炎分泌表型。

• DOI: 10.1152/ajpheart.00483.2023
• 发表时间: 2024
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Felisbino,MarinaB;Rubino,Marcello;Travers,JoshuaG;Schuetze,KatherineB;Lemieux,MadeleineE;Anseth,KristiS;Aguado,BrianA;McKinsey,TimothyA
• 通讯作者: McKinsey,TimothyA