Targeted therapeutic modulation of inflammatory cytokines through manipulation of noncoding RNA regulation of innate immunity in atopic dermatitis

通过操纵特应性皮炎先天免疫的非编码RNA调节炎症细胞因子的靶向治疗调节

• 批准号: 9912493
• 负责人: Kevin Chun-Kai Wang
• 金额: $ 39.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912493
• 关键词: 3-Dimensional; Acute; Address; Age; Animals; Architecture; Atopic Dermatitis; Behavior; Binding Proteins; Biological; Calcineurin inhibitor; Cell Line; Cell Nucleus; Cells; Chromatin; Chronic; Clinical; Complex; Cyclosporine; Cytokine Activation; Data; Defect; Development; Dimensions; Disease; Dose; Elements; Epigenetic Process; Event; Genes; Genetic Transcription; Genome; Genome engineering; Genomics; Human; IL4 gene; Immune; Immune Cell Activation; Immune Targeting; Immune response; Immunoprecipitation; Immunosuppression; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Interleukins; Lesion; Lymphoid Cell; Maintenance; Mass Spectrum Analysis; Mediator of activation protein; Modeling; Molecular; Molecular Conformation; Monitor; Morbidity - disease rate; Mus; Natural Immunity; Neurons; Noise; Nuclear; Nucleotides; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Phenotype; Pilot Projects; Play; Population; Proteins; RNA; Regulation; Resolution; Ribonucleoproteins; Role; Sensory; Skin; Source; Subcutaneous Injections; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Transcriptional Regulation; Untranslated RNA; chemokine; chromatin immunoprecipitation; chromosome conformation capture; chronic inflammatory skin; crosslink; cytokine; epigenetic regulation; immune activation; immunoregulation; in vivo; inflammatory modulation; inhibitor/antagonist; innovation; intravenous injection; keratinocyte differentiation; knock-down; mouse model; novel; precision medicine; promoter; prototype; response; skin disorder; targeted treatment

Atopic Dermatitis (AD), the most common chronic inflammatory skin disorder worldwide, is driven by both terminal keratinocyte differentiation defects and strong type 2 immune responses. What controls AD disease activity? Why is its response to therapy different from patient to patient? These are poorly understood problems and presents a large unmet need for both effective and safe therapeutics. In this project we seek to provide a molecular handle to explain some of these fundamental questions, by addressing a potentially under-explored source of immune regulation represented by epigenetic mechanisms. Our paradigm-shifting hypothesis centers on the epigenetic regulation of the immune response implicated in the pathogenesis of AD, and on a newly identified class of long noncoding RNAs (lncRNAs), the immune gene priming lncRNAs (IPLs), that exploit pre-formed chromatin topology at specific cytokine nuclear compartments to facilitate their epigenetic priming and activation. We propose to test and expand our hypothesis using technological advances that only now make this possible. I outline here a plan to pursue this opportunity with 3 specific aims. In Aim 1 (the R61 phase), we will establish the upstream molecular events that coordinate the epigenetic state of inflammatory genes. We hypothesize that IPLs are critical mediators that directly interact with the 3-dimensional chromatin architecture to prime chemokine promoters and enhance the pro- inflammatory responses in innate immune cell activation. We will characterize the mechanisms through which IPLs regulate IL-4 and IL-13, keystone interleukins critical to the induction and perpetuation of the Type 2 response in AD. In Aim 2, we will identity novel protein components that directly interact with the IPLs to modulate the chromatin landscape. We will also perform chromosome conformation capture across the IL-4/IL-13 locus to establish whether changing levels of IPL-IL4/13 alters chromosomal looping across the locus. Lastly, in Aim 3 (R33 phase) we will test inhibitors that specifically target IPL-4/13 in established murine AD-like models that recapitulate human AD. The IPL inhibitors will also be evaluated for their effects on the sensory responses known to influence AD behavior, to modulate direct neuronal priming by Type 2 cytokines shown to be a key step in the pathogenesis of AD. Taken together, our data will directly establish how IPLs and 3-dimensional chromatin architecture act in a cooperative manner to reduce gene-intrinsic noise, and allow robust activation of innate immune genes. A more precise fine-tuning of chemokine transcription through direct manipulations of IPL activities represents a highly valuable therapeutic strategy to achieve tailored immunomodulation in AD.

特应性皮炎（AD）是全球最常见的慢性炎症性皮肤疾病， 由两个末端角质形成细胞分化缺陷和强2型免疫驱动 回答。是什么控制AD疾病活动？为什么其对治疗的反应与 病人？这些问题知之甚少，并且提出了很大的未满足需求 有效和安全的治疗学。在这个项目中，我们试图为 通过解决潜在的探索案例，解释其中一些基本问题 以表观遗传机制为代表的免疫调节来源。我们的范式转移 假设集中于与该免疫反应的表观遗传调节有关 AD的发病机理，以及新鉴定的长期非编码RNA（LNCRNA）类别 免疫基因启动LNCRNA（IPLS），在特定的 细胞因子核区室，以促进其表观遗传启动和激活。我们建议 使用技术进步来检验和扩展我们的假设，直到现在 可能的。我在这里概述了一个计划，以3个特定的目标来寻求这一机会。在AIM 1中（R61 阶段），我们将建立上游分子事件，以协调表观遗传状态 炎症基因。我们假设IPL是直接与之互动的关键介体 三维染色质结构，用于趋化因子启动子并增强促趋化因子的启动子 先天免疫细胞激活中的炎症反应。我们将表征机制 IPLS调节IL-4和IL-13，Keystone Interleukins对诱导至关重要 AD中2型响应的持续性。在AIM 2中，我们将识别新型蛋白质成分 直接与IPL相互作用以调节染色质景观。我们也会表演 跨IL-4/IL-13基因座捕获染色体构象，以确定是否改变 IPL-IL4/13的水平改变了整个基因座的染色体环。最后，在AIM 3（R33阶段）中 我们将测试专门针对IPL-4/13的抑制剂，以既定的鼠类广告样模型 概括人类广告。 IPL抑制剂还将评估其对感觉的影响 已知会影响AD行为的响应，以2型调节直接神经元启动 细胞因子证明是AD发病机理的关键步骤。综上所述，我们的数据将 直接建立IPL和3维染色质体系结构的合作方式 减少基因内噪声并允许固有免疫基因激活的方式。一个 通过直接操纵IPL活动，对趋化因子转录进行更精确的微调 代表了在AD中实现量身定制的免疫调节的一种高度有价值的治疗策略。