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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要舒张功能障碍 (DD) 的特征是左心室顺应性和舒张受损，与发生射血分数保留心力衰竭 (HFpEF) 的风险增加，这是一种破坏性综合征预后不良，目前的动态乙酰化治疗干预措施有限。组蛋白代表参与激活的染色质依赖性信号转导的关键组成部分心脏成纤维细胞 (CF) 的减少和细胞外基质沉积的增加，导致进行性 DD 和这些过程主要受组蛋白脱乙酰酶 (HDAC) 家族的调控。表观遗传调节酶，其药理抑制作用在 DD 情况下具有心脏保护作用；然而，关于 HDAC 亚型特异性和介导这种现象的分子机制知之甚少。该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和生物信息学技术检查 HDAC 抑制的细胞类型和亚型特异性（目标 1 和 2），以及抑制肌成纤维细胞中新型聚糖结合蛋白的治疗潜力（目标 3）在目标 1 和 2 中，申请人将与共同导师和顾问一起进行培训。单细胞全基因组下一代测序技术中的 K99 阶段，可表征染色质架构，一种基于流式细胞术的技术，用于表征炎症细胞，一种综合方法原代人类 CF 中的转录组学和蛋白质组学分析，以及基于遗传学的细胞类型方法特定基因消融，所有这些的总体目标是定义细胞特异性和分子机制在目标 3 中描述的 R00 阶段，申请人介导 HDAC 抑制的心脏保护特性。将利用在 K99 阶段获得的技能来研究抑制聚糖结合蛋白 Galectin-1，最近发现在小鼠 CF 群体中发生显着改变 DD 和 HDAC 抑制对肌成纤维细胞激活、心脏重塑和进展的影响申请者在表观遗传学、CF 生物学和此外，指导团队由国际专家组成。在心血管疾病表观遗传调控、临床 HFpEF、HF 小鼠模型和科罗拉多大学安舒茨医学院的新兴生物信息学技术。是协作和创新研究的典范，拥有包括人类心脏在内的优良基础设施生物样本库和出色的核心设施总而言之，是卓越的指导团队和机构。环境将为申请人发展成为独立研究者提供坚实的基础。此外，这种创新方法提供了令人兴奋的潜力，可以为迫切需要的发展做出贡献需要新的治疗策略来治疗心力衰竭。

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（0）

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：
发表时间：
2024-01-01
期刊：
影响因子：
0
作者：
Felisbino, Marina B;Rubino, Marcello;Travers, Joshua G;Schuetze, Katherine B;Lemieux, Madeleine E;Anseth, Kristi S;Aguado, Brian A;McKinsey, Timothy A
通讯作者：
McKinsey, Timothy A