MicroRNA as a target for fetal hemoglobin inducing agents in sickle cell disease

MicroRNA 作为镰状细胞病胎儿血红蛋白诱导剂的靶标

• 批准号: 10329933
• 负责人: Ying He
• 金额: $ 24.9万
• 依托单位: OSU CENTER FOR HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329933
• 关键词: Acute; Acute Pain; Address; Adult; Affect; African; Aftercare; American; Behavioral Paradigm; Biogenesis; Biological Markers; Clinical; Companions; Complex; Data; Development; Development Plans; Disease; Disease Progression; Dose; Encapsulated; Epigenetic Process; Erythroblasts; FDA approved; Fetal Hemoglobin; Gene Expression; Genes; Genetic Transcription; Globin; Goals; Hemolytic Anemia; Hispanic; Intervention; Life; Lysine; Maps; Measures; Mediating; Medical; Mentors; Methods; MicroRNAs; Molecular; Mus; Neuropathogenesis; Organ; Outcome; Outcome Measure; Pain; Papio; Pathology; Pathway interactions; Patients; Persistent pain; Persons; Pharmaceutical Preparations; Pharmacology; Production; Quality of life; Recurrence; Refractory; Regulation; Research; Research Personnel; Research Proposals; Role; SNAP receptor; Severities; Severity of illness; Sickle Cell; Sickle Cell Anemia; Symptoms; Testing; Therapeutic Agents; Time; Training; Work; career; career development; chronic pain; design; effective therapy; exosome; hydroxyurea; improved; inhibitor; innovation; knock-down; mortality; mouse model; novel; pain relief; programs; therapeutic target; therapy outcome

My long-term research goal is to develop effective pharmacological interventions that can alleviate disease progression and improve the quality of life for patients with sickle cell disease (SCD). Approximately 100,000 Americans–primarily African or Hispanic background–suffer from SCD, featured with recurrent episodes of acute vaso-occlusion, hemolytic anemia, and progressive organ damage. The only FDA-approved drug for SCD, hydroxyurea, induces fetal hemoglobin (HbF) production, decreases disease severity, and benefits overall mortality. However, the ability of hydroxyurea to induce HbF is highly variable, with over 50% of patients do not respond to hydroxyurea. There remains a critical and urgent need to identify additional HbF-inducing therapeutic agents. Among a large number of epigenetic mechanisms that have been explored for -globin gene reactivation, lysine specific demethylase1 (LSD1) has emerged as an attractive target. Research from our group showed that RN-1, a selective inhibitor of LSD1 significantly stimulated -globin gene transcription and reduced disease pathology in a mouse model of SCD. Ongoing study in baboons has confirmed enhanced HbF production by RN-1. However, the mechanism by which LSD1 inhibitor induces HbF is not known. Moreover, recent studies on microRNA (miRNA) have shed lights on the identification of novel HbF inducing agents. Suppression of let- 7a miRNA significantly increased HbF expression in adult human erythroblasts. My own work has identified let- 7 as an epigenetic mechanism in the neuropathogenesis of SCD. Uniquely, my preliminary data suggest that RN-1 improves SCD by mechanisms that involve circulating exosomal miRNA. Therefore, it is scientific compelling to elucidate the intriguing interactions between LSD1 and let-7 miRNA in SCD. While much of the research has been focused on ameliorating clinical severity of SCD, pain can represent as another major therapeutic outcome. SCD is not only characterized by acute exacerbations of pain (acute pain), but also intractable persistent pain throughout a patient's life. Chronic pain is refractory to current medications and represents a significant unmet medical challenge. Increased levels of HbF can alleviate disease symptoms and decrease acute painful episodes. However, scientific evidence for an effect of hydroxyurea on chronic pain in SCD is lacking. In this application, I propose to employ pain as an innovative approach to measure the outcome of inducing HbF. I will test the hypothesis that let-7 miRNA is a novel target of LSD1 to modulate HbF silencing and chronic pain in SCD. By identifying molecular and epigenetic mechanisms of LSD1 and let-7 miRNA in SCD, specific targeting of these mechanisms holds great promise of designing effective therapies that can benefit patients with SCD. Successful completion of the study will not only achieve my training objective to transit to an independent academic investigator, but also build up a strong scientific framework for future research and R01 applications

我的长期研究目标是开发有效的药物干预，可以缓解疾病 改善镰状细胞病（SCD）患者的生活质量。约10万 美国人-主要是非洲或西班牙裔背景-患有SCD，其特征是反复发作， 急性血管闭塞、溶血性贫血和进行性器官损伤。唯一一种FDA批准的 SCD，羟基脲，诱导胎儿血红蛋白（HbF）的生产，降低疾病的严重程度， 总死亡率。然而，羟基脲诱导HbF的能力是高度可变的，超过50%的患者 对羟基脲没有反应。仍然迫切需要确定额外的HbF诱导因子。 治疗剂。 在已经探索的大量β-珠蛋白基因再激活的表观遗传机制中， 赖氨酸特异性脱甲基酶1（LSD 1）已经成为一个有吸引力的靶点。我们小组的研究表明 RN-1，一种LSD 1的选择性抑制剂，显著刺激β-珠蛋白基因转录， 在SCD的小鼠模型中的病理学。正在进行的狒狒研究证实， RN-1然而，LSD 1抑制剂诱导HbF的机制尚不清楚。此外，最近的研究 microRNA（miRNA）的研究为新型HbF诱导剂的鉴定提供了线索。禁止出租- 7a miRNA显著增加成人成红细胞中的HbF表达。我自己的工作已经确定了让- 7作为SCD神经发病机制中的表观遗传机制。独特的是，我的初步数据表明， RN-1通过涉及循环外泌体miRNA的机制改善SCD。因此，它是科学的 令人信服的是，阐明了SCD中LSD 1和let-7 miRNA之间有趣的相互作用。 虽然大部分研究都集中在改善SCD的临床严重程度上，但疼痛可以代表 作为另一个主要的治疗结果。SCD的特征不仅在于疼痛的急性加重（急性 疼痛），而且在患者的一生中顽固性持续疼痛。慢性疼痛对电流不敏感 这是一个重大的医学挑战，尚未得到解决。HbF水平升高可缓解 疾病症状和减少急性疼痛发作。然而，科学证据表明， 羟基脲对SCD患者慢性疼痛的疗效缺乏。在这个应用程序中，我建议采用疼痛作为一种创新的 方法来测量诱导HbF的结果。我将验证let-7 miRNA是一个新靶点的假设， LSD 1的表达调节SCD中HbF沉默和慢性疼痛。 通过鉴定LSD 1和let-7 miRNA在SCD中的分子和表观遗传机制， 这些机制在设计可使SCD患者受益的有效疗法方面具有很大的希望。 成功完成学习不仅可以实现我的培训目标， 学术研究人员，而且还建立了一个强大的科学框架，为未来的研究和R 01的应用