Aging and estrogen-dependent HDAC2 regulation: implications in cardiac injury

衰老和雌激素依赖性 HDAC2 调节：对心脏损伤的影响

• 批准号: 10593342
• 负责人: Prerna Kumar
• 金额: $ 7.6万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593342
• 关键词: Age; Aging; Binding; Biochemical; Bioinformatics; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell model; Clinical Trials; Data; Dependence; Dose; Echocardiography; Elderly; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Enzymes; Epigenetic Process; Equilibrium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Family; Female; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; HDAC2 gene; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart Injuries; Histology; Histone Deacetylase; Hormonal; Hormone replacement therapy; Human; Intervention; Knowledge; Measurement; Mediating; Menopause; Mission; Modeling; Molecular; Mus; National Institute on Aging; Nucleic Acid Regulatory Sequences; Outcome; Ovariectomy; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Play; Population; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Premenopause; Prevention; Proteins; Public Health; Regulation; Repression; Research; Response Elements; Risk Factors; Risk Reduction; Role; Signal Transduction; Stress; Techniques; Tissues; United States National Institutes of Health; Ventricular; Woman; age related; aged; cardioprotection; cardiovascular disorder risk; clinical development; combinatorial; design; digital; disorder risk; expectation; falls; female sex hormone; gene repression; heart function; human female; improved; in vivo; innovation; mRNA Expression; male; menopausal aging; novel; pathological aging; prevent; promoter; protective effect; public health relevance; receptor; research and development; response; sex; therapeutic target; trait

Project Summary The risk of cardiovascular disease (CVD) increases in females with aging and falling estrogen (E2) levels during menopause, yet the beneficial effects of postmenopausal hormone-replacement therapy (HRT) on reducing the risk remain controversial. Estrogen mediates its protective effects by inducing its receptor ERα binding to E2-target genes. Dysregulation of epigenetic enzymes like histone deacetylases (HDACs) are implicated in pathological aging and class I HDAC2 functions as a positive regulator of cardiac hypertrophy (CH) in response to stress. The long-term research goal is to contribute toward the development of clinically useful mechanism-based interventions to treating or preventing CVD in postmenopausal aging females. The overall objective for this R03 application is to establish proof of concept of age dependent E2/ERα signaling regulating HDAC2 expression in heart under physiological and pathophysiological conditions. The central hypothesis is that endogenous E2/ERα signaling is cardioprotective through the inhibition of HDAC2 expression in premenopausal females. The rationale underlying this project is that proof of concept of age- dependent E2/ERα-mediated repression of HDAC2 expression and cardio protection will enable subsequent definitive R01 studies aimed at designing strategies to treat or prevent heart diseases in aging females. The central hypothesis will be examined with 2 Specific Aims: 1) Identify age-dependent effects of E2/ER alpha on cardiac HDAC2 expression. Under this aim a) cultured human CM (HCM) isolated from normal male, pre and postmenopausal female ventricular heart tissue will be utilized to establish transcriptional repression of HDAC2 gene via actions of E2/ERα and (b) young and old female and male mice heart tissues will be utilized to determine age- and sex-dependent regulation of cardiac ERs and HDAC2 gene expression and activity by novel Droplet Digital PCR (ddPCR), molecular and biochemical techniques. 2) Determine the functional consequences of ovariectomy and E2 on cardiac function and regulation of HDAC2 expression/activity. In this aim, effects of E2 on HDAC2 repression will be studied in drug–induced CH in ovariectomized (young and aged) female mice by utilizing echocardiography, systolic blood pressure measurements, ELISA, histology, and gene expression studies. The research proposed in this application is innovative in the applicant's opinion, because it utilizes new ddPCR technique and studies a novel regulatory mechanism of E2/ERα-mediated HDAC2 repression at the transcription level in heart. This will lead to define new E2/ERα transcriptional target and its functional role in the heart of young and aging females. The proposed research is significant because it is expected to provide strong scientific justification for the continued research and development of combinatorial drug with E2 for aging females.

项目摘要 随着年龄的增长和雌激素水平的下降，女性患心血管疾病的风险增加 在绝经期间，绝经后激素替代疗法(HRT)对 降低风险仍存在争议。雌激素通过诱导其受体ERα介导其保护作用 与E2靶基因结合。组蛋白脱乙酰酶(HDACs)等表观遗传酶的失调 HDAC2参与病理性衰老和I类心肌肥厚的正向调节作用 (Ch)对压力的反应。长期的研究目标是为临床医学的发展做出贡献。 有效的基于机制的干预措施治疗或预防绝经后老年女性的心血管疾病。这个 此R03应用程序的总体目标是建立年龄相关的E2/ERα信号概念的证据 在生理和病理生理条件下调节心脏中HDAC2的表达。中环 假设内源性E2/ERα信号通过抑制HDAC2发挥心脏保护作用 在绝经前女性中的表达。这个项目的基本原理是对年龄概念的证明- 依赖的E2/ERα介导的抑制HDAC2表达和心脏保护将使随后的 权威性R01研究旨在设计治疗或预防老年女性心脏病的策略。这个 中心假说将以两个具体目标进行检验：1)确定E2/ERα的年龄依赖效应 对心脏HDAC2表达的影响。在这一目标下，a)培养的人CM(HCM)从正常男性， 绝经后的女性心脏组织将被用来建立转录抑制 HDAC2基因通过E2/ERα的作用和(B)幼年和老年雌性和雄性小鼠心脏组织将被 用于确定心脏ER和HDAC2基因表达的年龄和性别依赖性调节以及 通过新型液滴数字聚合酶链式反应(DdPCR)、分子和生化技术进行活性检测。2)确定 卵巢切除和雌二醇对心功能的影响及HDAC2的调节 表情/活动。为此，我们将研究雌二醇对药物诱导的中国仓鼠HDAC2抑制的影响。 应用超声心动图、收缩压检测去卵巢雌性小鼠(青年和老年) 测量、酶联免疫吸附试验、组织学和基因表达研究。这项申请中提出的研究是 申请人认为是创新的，因为它利用了新的ddPCR技术并研究了一种新的 E_2/ERα介导的hDAC2在心脏转录水平的调控机制这将是 Lead定义新的E2/ERα转录靶点及其在年轻和衰老心脏中的功能作用 女性。这项拟议的研究意义重大，因为它有望提供强有力的科学依据。 用于继续研究和开发针对老年女性的雌二醇组合药。