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.

项目摘要/摘要 遗传学是对炎症性肠病（IBD）的敏感性的基础 低一致性率，表明环境的普遍作用以及可能的表观基因组。 表观遗传酶的失调是癌症的复发性和前哨事件，使蛋白质“写入”， “擦除”和“阅读”表观基因组最有望的，并专心地追求药物发现的目标 今天。尽管如此，关于表观遗传酶的改变几乎一无所知 免疫障碍，包括IBD。拟议研究的长期目标是确定 表观遗传改变会影响IBD，并准确地破译引起疾病的机制以更好 治疗策略。斑点蛋白140（SP140）是一种具有免疫限制的表观遗传“读取器”蛋白 表达。 SP140中的单个核苷酸多态性（SNP）与克罗恩病（CD）（1，2）相关 但是，SP140的功能和SP140 SNP的后果尚不清楚。我们发现CD- 相关的SP140 SNP导致SP140 mRNA剪接改变和SP140蛋白的损失（4）。我们也是 将SP140识别为巨噬细胞转录程序的关键编排，对于细胞身份必不可少 和功能（4）。此外，我们发现小鼠SP140的造血耗竭加剧了结肠炎和 由于遗传变异而导致SP140的损失导致CD的一部分，其特征是抑制先天的 免疫（4）。本提案的总体目标，这是实现我们的下一步 长期目标是利用来自IBD遗传学联盟的多个资源来确切定义 SP140在介导的受保护的先天和适应性免疫抑制方面，朝向共生微生物，以及 确定SP140的常见或稀有变体如何影响这些分配功能。 通过引人注目的初步数据的指导，我们的假设将以三个特定的目的进行检验：1）阐明 SP140在受保护的先天免疫中对共生微生物的作用； 2）定义SP140在 B细胞的发育和功能； 3）确定SP140作为表观遗传调节剂的机制。在下面 我们将在小鼠中使用诱导的SP140部署系统的第一个和第二个目标，并并行检查 携带SP140变异的患者的细胞。对于目标3，我们将确定精确机制 SP140调节免疫细胞的身份和功能。在申请人意见中，这种方法是创新的 因为这项工作将是改变表观遗传酶表达和功能的第一批描述之一 免疫介导的疾病的驱动力。拟议的研究很重要，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，并且 这些疾病的分层。最终，这种知识有可能垂直提高 开发用于CD和其他免疫疾病的新型疗法。