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

我的长期研究目标是开发能够减轻疾病的有效药物干预措施 改善镰状细胞病(SCD)患者的生活质量。大约100,000 美国人-主要是非洲或西班牙裔背景-患有SCD，以反复发作为特征 急性血管闭塞、溶血性贫血和进行性器官损害。FDA批准的唯一一种治疗 SCD，羟基尿素，诱导胎儿血红蛋白(HBF)的产生，降低疾病严重程度，并有益于 总死亡率。然而，羟基脲诱导HBF的能力是高度不同的，超过50%的患者 对羟基脲没有反应。仍然迫切需要确定更多诱发HBF的因素 治疗剂。 在已探索的-珠蛋白基因重新激活的大量表观遗传机制中， 赖氨酸特异性去甲基酶1(LSD1)已成为一个有吸引力的靶点。我们小组的研究表明 LSD1的选择性抑制剂RN-1显著刺激-珠蛋白基因转录并减少疾病 SCD小鼠模型的病理学研究。正在进行的对狒狒的研究证实，通过 RN-1。然而，LSD1抑制剂诱导HBF的机制尚不清楚。此外，最近的研究 对microRNA(MiRNA)的研究为新的HBF诱导剂的鉴定提供了线索。抑制LET- 7A miRNA显著增加成人红细胞HBF的表达。我自己的工作已经确定了LET- 7在SCD的神经发病机制中起表观遗传作用。唯一的是，我的初步数据表明 RN-1通过涉及循环外体miRNA的机制改善SCD。因此，它是科学的。 迫切需要阐明在SCD中LSD1和let-7miRNA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的特征不仅是疼痛的急性加重(急性 疼痛)，但也是患者一生中顽固的持续性疼痛。慢性疼痛难治性 这是一项尚未得到满足的重大医学挑战。增加HBF水平可以缓解 减少疾病症状，减少急性疼痛发作。然而，科学证据表明， 羟基脲对SCD慢性疼痛的治疗作用缺乏。在本应用程序中，我建议将Pain作为一种创新的 测量诱发高压性血流量结果的方法。我将测试let-7miRNA是一个新靶点的假设 LSD1对SCD患者HBF沉默和慢性疼痛的调节作用。 通过鉴定LSD1和let-7miRNA在SCD中的分子和表观遗传学机制，特异性靶向 这些机制很有希望设计出有效的治疗方法，使SCD患者受益。 顺利完成这项研究不仅将实现我的培养目标，而且将过渡到独立 学术研究人员，也为未来的研究和R01应用建立了强大的科学框架

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