Impact of Aiolos on intestinal intraepithelial lymphocytes

Aiolos 对肠上皮内淋巴细胞的影响

• 批准号: 10369492
• 负责人: Kentaro Yomogida
• 金额: $ 16.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369492
• 关键词: Address; Autoimmune Diseases; B-Cell Activation; Binding; Binding Sites; Biological Assay; CD94 Antigen; Cell Maturation; Chemical Exposure; Chromatin; Chronic; Chronic Disease; Clinical; Colitis; Data; Dextrans; Diet; Disease; Enhancers; Enzymes; Epigenetic Process; Epithelial; Flare; Gastrointestinal tract structure; Genes; Genetic Predisposition to Disease; Granzyme; Heterogeneity; Immune; Immune response; Infection; Inflammation; Inflammatory Bowel Diseases; Interferon Type II; Interferons; Intestines; Invaded; Lead; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Maintenance; Modeling; Modification; Mucositis; Mus; Mutation; Natural Killer Cells; Pathogenesis; Pathologic; Patients; Play; Role; Salmonella typhimurium; Sodium; Sodium Chloride; Techniques; Tissues; Transcription Repressor; Transposase; Zinc Fingers; cell type; chromatin remodeling; cytokine; cytotoxic; defined contribution; dextran sulfate sodium induced colitis; enteric infection; gut homeostasis; gut inflammation; histone modification; insight; intestinal epithelium; intraepithelial; microbiota; new therapeutic target; novel; novel therapeutics; nuclease; pathogen; response; tissue repair; transcription factor; treatment response

Project Summary/Abstract Inflammatory bowel disease (IBD) is a common disorder that causes inflammation predominantly in the digestive tract. Although treatment options have expanded in the past two decades, a significant portion of patients still suffer from poor treatment response and chronic clinical courses. Various responses to currently available therapy are in part due to the heterogeneity of pathogenesis, and novel mechanistic insight that could lead to new therapeutic options is critically needed. Intestinal intraepithelial lymphocytes (IELs) are a heterogeneous group of tissue-resident lymphocytes, and pathological activation of IELs is implicated in the exacerbation of IBD. However, the regulatory mechanisms of IELs during activation are not well understood. Aiolos, a transcription factor encoded by Ikzf3, is expressed exclusively in lymphocytes, and contributes to B cell activation and NK cell maturation. Aiolos mutations are implicated in various autoimmune diseases including IBD, but the roles of Aiolos in IELs or gut homeostasis have not been studied in the past. I discovered that Aiolos is highly expressed in IELs and that Aiolos-deficient IELs are more activated and express higher levels of activation markers (NK receptors) and cytokines (interferon-g and granzymes) compared to wild-type cells. These preliminary results indicate that Aiolos strongly suppresses IEL activation. Since Aiolos is a transcription factor modulating chromatin remodeling, I hypothesize that Aiolos binds to the enhancer regions of genes associated with IEL activation and controls their expression by altering epigenetic modifications. Additionally, since Aiolos potently regulates IEL activation, I hypothesize that Aiolos-deficient IELs modulate the host response to colitogenic infection and intestinal inflammation. In this proposed project, I will address these hypotheses with the following aims: (Aim 1) to identify Aiolos binding sites and define the contribution of Aiolos to epigenetic landscape in IELs, and (Aim 2) to investigate the impact of Aiolos-deficient IELs during mucosal inflammation. In Aim 1, I will utilize state-of- the-art epigenetic techniques to examine Aiolos binding sites in wild-type IELs and investigate how Aiolos deficiency alters epigenetic modifications in IELs. I plan to examine differences of epigenetic modifications between Aiolos-deficient IELs and wild-type IELs by comparing open chromatin regions and histone modifications. In Aim 2, I will challenge mice with Aiolos-deficient IELs and mice with wild-type IELs with Salmonella typhimurium and dextran sodium salt-induced colitis to delineate the impact of Aiolos-deficient IELs on host responses to intestinal infection and inflammation. Taken together, this project will contribute to profiling cis-regulatory circuits of IELs and could advance our understanding of the pathogenesis of IBD, which could eventually lead to the identification of new therapeutic targets.

项目摘要/摘要 炎症性肠病(IBD)是一种常见的疾病，主要引起消化系统的炎症。 一条小路。尽管治疗方案在过去20年里有所扩大，但仍有相当一部分患者 患有治疗反应差和慢性临床病程。对当前可用的各种响应 治疗在一定程度上是由于发病机制的异质性，以及可能导致 迫切需要新的治疗方案。肠道上皮内淋巴细胞(IEL)是一种异质性 IELs的病理性激活与IBD的加重有关。 然而，IEL在激活过程中的调节机制还不是很清楚。Aiolos，抄本 由IKZF3编码的因子仅在淋巴细胞中表达，并有助于B细胞激活和NK细胞 成熟。Aiolos突变与包括IBD在内的各种自身免疫性疾病有关，但Aiolos的作用 在IEL或肠道内，动态平衡在过去还没有被研究过。我发现Aiolos在IELs中高度表达 Aiolos缺陷的IEL更活跃，表达更高水平的激活标记(NK受体) 和细胞因子(干扰素-g和颗粒酶)相比较。这些初步结果表明 Aiolos强烈抑制IEL的激活。由于Aiolos是一种调节染色质的转录因子 重塑，我假设Aiolos与IEL激活相关基因的增强子区域结合，并 通过改变表观遗传修饰来控制它们的表达。此外，由于Aiolos有力地规范了IEL 激活，我假设Aiolos缺陷的IEL调节宿主对结肠源性感染的反应，并 肠道发炎。在这个拟议的项目中，我将以以下目标来解决这些假设：(AIM 1)确定Aiolos结合位点并确定Aiolos对IELs表观遗传景观的贡献，以及(Aim 2)探讨Aiolos缺陷的IEL在黏膜炎症中的作用。在目标1中，我将利用- 检测野生型IEL中Aiolos结合位点的最先进的表观遗传学技术，并研究Aiolos如何 缺乏症改变了IEL的表观遗传修饰。我计划研究表观遗传修饰的差异 Aiolos缺陷型IEL与野生型IEL开放染色质区域和组蛋白的比较 修改。在目标2中，我将挑战Aiolos缺陷IELs小鼠和野生型IELs小鼠 鼠伤寒沙门氏菌和葡聚糖钠盐诱导的结肠炎对Aiolos缺陷IEL的影响 关于宿主对肠道感染和炎症的反应。综上所述，该项目将有助于分析 IELs的顺式调节电路，可以促进我们对IBD发病机制的理解，这可能 最终导致新的治疗靶点的确定。