Design and development of HDAC11-specific chemical inhibitors for disease treatments

用于疾病治疗的 HDAC11 特异性化学抑制剂的设计和开发

• 批准号: 10581571
• 负责人: Hening Lin
• 金额: $ 69.75万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581571
• 关键词: Acute; Adverse effects; Affect; Autoimmune Diseases; Biochemical; Biological; Biological Process; CNS Demyelinating Autoimmune Diseases; Cells; Chemicals; Chronic; Chronic Progressive Multiple Sclerosis; Clinical; Clinical Trials; Collaborations; Data; Deacetylase; Deacetylation; Development; Disease; Disease Management; Enzyme Inhibitor Drugs; Enzymes; Experimental Autoimmune Encephalomyelitis; Future; Genetic Models; Goals; HDAC11 gene; HDAC4 gene; Health; Healthcare; Histone Deacetylase; Immune; Interferon Type I; Interferons; Knockout Mice; Knowledge; Laboratories; Lysine; Mediating; Mission; Modeling; Multiple Sclerosis; Mus; Nerve Degeneration; Pathogenesis; Pathology; Persons; Pharmaceutical Preparations; Phase; Physiological; Proteomics; Recombinant Interferon Beta; Relapsing-Remitting Multiple Sclerosis; Reporting; Research; Role; Severity of illness; Side; Signal Transduction; Spinal Cord; Symptoms; Testing; Therapeutic; Time; United States National Institutes of Health; Universities; Virus Diseases; Washington; Work; acyl group; alternative treatment; cell motility; central nervous system demyelinating disorder; design; disability; effective therapy; fatty acylation; immune cell infiltrate; improved; in vivo; inhibitor; insight; mouse model; multidisciplinary; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; new therapeutic target; novel; novel therapeutic intervention; prototype; small molecule; targeted treatment; tool; treatment strategy; young adult

Project Summary This resubmission proposal aims to elucidate the role of a histone deacetylase, HDAC11, in diseases such as multiple sclerosis (MS), and to establish HDAC11 inhibition as a potentially effective new treatment strategy for diseases including MS. MS is a chronic, immune-mediated demyelinating disease of the central nervous system. Like many autoimmune disorders, it presently has no known cure, and current drugs available for managing this disease are only effective early on and are accompanied by many adverse effects. The disease mechanism of MS remains unclear, and no effective targeted therapy is available for chronic progressive MS. Our preliminary studies show that deletion of HDAC11 ameliorates clinical symptoms in a mouse model of MS. In parallel, we discovered a novel HDAC11 enzymatic activity that is >10,000-fold more efficient than its deacetylase activity. This novel activity allows us to begin to uncover physiologic substrates of HDAC11, which in turn will help to uncover the biological mechanisms of HDAC11’s actions. One of the goals of this research is to investigate how this newly discovered enzymatic activity underlies the immune-regulatory function of HDAC11 in MS. Knowledge gained from these studies will help to further understand the disease mechanism of MS and to develop better therapeutics. Because the discovery of a novel HDAC11 activity has enabled us to develop, for the first time, HDAC11-specific inhibitors, the chief objective is to further improve these inhibitors and test whether they can be used to treat diseases such as MS in our established mouse models. Our multidisciplinary team has expertise in all aspects needed to make this project successful. Overall, the proposed studies in this application will not only yield a better understanding of HDAC11’s function in health and diseases, but may also result in a first prototype targeted therapy for the treatment of chronic progressive MS, and possibly other diseases as well.

项目摘要 这个重新提交的提案旨在阐明组蛋白去乙酰化酶HDAC11在疾病中的作用， 作为多发性硬化症（MS），并建立HDAC11抑制作为一种潜在有效的新的治疗策略 MS是一种慢性、免疫介导的中枢神经脱髓鞘疾病， 系统像许多自身免疫性疾病一样，它目前还没有已知的治愈方法，目前的药物可用于治疗 控制这种疾病的方法只能在早期有效，并伴随着许多不良影响。疾病 MS的发病机制尚不清楚，并且没有有效的靶向治疗可用于慢性进行性MS。 我们的初步研究表明，HDAC11的缺失改善了MS小鼠模型的临床症状。 与此同时，我们发现了一种新的HDAC11酶活性，其效率是其活性的10，000倍。 脱乙酰酶活性这种新的活性使我们能够开始揭示HDAC 11的生理底物， 反过来将有助于揭示HDAC11作用的生物学机制。这项研究的目标之一是 研究这种新发现的酶活性如何成为免疫调节功能的基础， HDAC 11在MS中的作用，这些研究将有助于进一步了解疾病机制 并开发更好的治疗方法。因为新的HDAC11活性的发现使我们能够 首次开发HDAC11特异性抑制剂，主要目标是进一步改善这些抑制剂 并在我们建立的小鼠模型中测试它们是否可用于治疗MS等疾病。我们 多学科团队拥有使该项目成功所需的所有方面的专业知识。总体看 在这项应用中提出的研究不仅可以更好地了解HDAC 11在健康中的功能， 和疾病，但也可能导致第一个原型靶向治疗慢性进展性 MS，也可能是其他疾病。