Understanding the role of Epigenetic Reader SP140 in IBD

了解表观遗传 Reader SP140 在 IBD 中的作用

• 批准号: 10242706
• 负责人: Robert McCullough Anthony
• 金额: $ 29.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242706
• 关键词: Advanced Development; B-Cell Development; B-Lymphocytes; Bacteria; Cells; Chronic Lymphocytic Leukemia; Colitis; Crohn' s disease; DNA; Data; Development; Disease; Environment; Enzymes; Epigenetic Process; Event; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genetic Variation; Goals; Hematopoietic; Histones; Human; Immune; Immune System Diseases; Immune response; Incidence; Inflammation; Inflammatory Bowel Diseases; Intestines; Kinetics; Knowledge; Lead; Maintenance; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Messenger RNA; Modeling; Modification; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Outcome; Patients; Peripheral Blood Mononuclear Cell; Predisposition; Prevention; Proteins; Proteome; Public Health; RNA Splicing; Reader; Recurrence; Repression; Research; Resources; Role; Sentinel; Signal Transduction; Single Nucleotide Polymorphism; Stratification; System; Testing; Therapeutic; Topoisomerase; Topoisomerase Inhibitors; Translating; Variant; Virus; Work; Writing; adaptive immunity; base; cell type; commensal bacteria; drug discovery; dysbiosis; epigenome; helicase; innovation; macrophage; microorganism; novel; novel therapeutics; programs; rare variant; virtual

Project Summary/Abstract Genetics underlie susceptibility to inflammatory bowel disease (IBD) but the rapid rise in incidence, as well as low concordance rates, point to a prevalent role for the environment and possibly the epigenome. Dysregulation of epigenetic enzymes is a recurrent and sentinel event in cancer, making proteins that “write”, “erase” and “read” the epigenome some of the most promising and intently pursued targets in drug discovery today. Despite this, virtually nothing is known about how altered epigenetic enzymes contribute to immunological disorders, including IBD. The long-term goal of the proposed research is to determine how epigenetic alterations influence IBD and accurately decipher the disease-causing mechanisms for better therapeutic strategies. Speckled Protein 140 (SP140) is an epigenetic “reader” protein with immune-restricted expression. Single nucleotide Polymorphisms (SNPs) within SP140 associate with Crohn's disease (CD) (1, 2) however, the function of SP140 and the consequences of SP140 SNPs have remained unclear. We found CD- associated SP140 SNPs resulted in altered SP140 mRNA splicing and a loss of SP140 protein (4). We also identified SP140 as a key orchestrator of macrophage transcriptional programs essential for cellular identity and function (4). Furthermore, we found that hematopoietic depletion of Sp140 in mice exacerbated colitis and a loss of SP140 due to genetic variation contributed to a subset of CD characterized by suppressed innate immunity (4). The overall objective of the present proposal, which is the next step towards attainment of our long-term goal, is to utilize multiple resources from the IBD Genetics Consortium to precisely define the roles of SP140 in mediating protective innate and adaptive immunity toward commensal microorganisms, and determine how common or rare variants of SP140 impacts these ascribed functions. Guided by compelling preliminary data, our hypotheses will be tested in three specific aims: 1) Elucidate the role of SP140 in protective innate immunity toward commensal microorganisms; 2) Define the role of SP140 in B cell development and function; and 3) Determine the mechanism of SP140 as an epigenetic regulator. Under the first and second aims we will utilize our inducible SP140 depletion system in mice and in parallel examine cells from patients carrying SP140 variants. For aim 3 we will determine the precise mechanism by which SP140 regulates immune cell identity and function. The approach is innovative in the applicant's opinion because the work will be one of the first descriptions of altered epigenetic enzyme expression and function as a driver of immune-mediated disease. The proposed research is significant because SP140 variants are associated with CD, MS and CLL so understanding the function of SP140 will aid understanding of, and stratification of, these diseases. Ultimately, such knowledge has the potential to vertically advance development of novel therapeutics for CD and other immune disorders.

项目总结/摘要 遗传学是炎症性肠病（IBD）易感性的基础，但发病率的迅速上升，以及 低一致率，指出环境和可能的表观基因组的普遍作用。 表观遗传酶的失调是癌症中的一种复发性和哨兵事件，使蛋白质“写”， “擦除”和“读取”表观基因组是药物发现中最有前途和最受关注的目标 今天尽管如此，几乎没有人知道改变的表观遗传酶如何有助于 免疫性疾病，包括IBD。拟议研究的长期目标是确定如何 表观遗传改变影响IBD，并准确地解释致病机制， 治疗策略斑点蛋白140（SP140）是一种表观遗传“阅读器”蛋白，具有免疫限制性功能。 表情SP140内的单核苷酸多态性（SNP）与克罗恩病（CD）相关（1，2） 然而，SP140的功能和SP140 SNPs的后果仍然不清楚。我们找到了CD- 相关的SP140 SNP导致SP140 mRNA剪接改变和SP140蛋白丢失（4）。我们也 确定SP140是细胞身份所必需的巨噬细胞转录程序的关键协调者 函数（4）。此外，我们发现小鼠中Sp140的造血耗竭加剧了结肠炎， 由于遗传变异导致的SP140缺失导致CD亚群，其特征在于先天性抑制 免疫（4）。本建议的总体目标是实现我们的目标的下一步， 长期目标是利用IBD遗传学联盟的多种资源，精确定义以下方面的作用： SP140介导对肠道微生物的保护性先天免疫和适应性免疫， 确定SP140的常见或罕见变体如何影响这些归因功能。 在令人信服的初步数据的指导下，我们的假设将在三个具体目标中进行测试：1）阐明 SP140在保护机体对微生物的天然免疫中的作用; 2）确定SP140在 B细胞发育和功能; 3）确定SP 140作为表观遗传调节剂的机制。下 第一个和第二个目标，我们将利用我们的诱导型SP140耗竭系统在小鼠和平行检查 来自携带SP140变异体的患者的细胞。对于目标3，我们将确定精确的机制， SP140调节免疫细胞的身份和功能。申请人认为，该方法具有创新性 因为这项工作将是改变表观遗传酶表达和功能的第一个描述之一， 免疫介导疾病的驱动因素。这项研究意义重大，因为SP140变体是 与CD，MS和CLL相关，因此了解SP140的功能将有助于理解， 这些疾病的分类。最终，这些知识有可能纵向推进 开发用于CD和其他免疫疾病的新疗法。