The Role of Estrogen Receptor Alpha Variant Size and Localization in Modulating TLR7-Induced Inflammation

雌激素受体 α 变体大小和定位在调节 TLR7 诱导的炎症中的作用

基本信息

批准号：
10365365
负责人：
Melissa A Cunningham
金额：
$ 38.47万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-14 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365365
关键词：
AF2 Address Affect Age Anti-Inflammatory Agents Antigen-Antibody Complex Antiinflammatory Effect Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biological Blood Vessels Bone Marrow Cell Line Cell membrane Cell physiology Cells Chromatin DNA Binding Data Dendritic Cells Deposition Development Disease Dose End stage renal failure Environmental Exposure Epidemiology Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptors Estrogens Event Female Genes Genetic Transcription Genomics Goals Gonadal Steroid Hormones Human Immune Immune Targeting Immune response In Vitro Incidence Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Innate Immune Response Interferon Gamma Receptor Beta Chain Investigation Kidney Kidney Diseases Length Ligand Binding Domain Location Lupus Lupus Nephritis Mediating Membrane Mus Mutant Strains Mice Nephritis Nuclear Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Predisposition Property Protein Isoforms Proteins Proteinuria Puberty Race Reporting Research Risk Factors Role Sampling Selective Estrogen Receptor Modulators Serum Sex Bias Sex Chromosomes Signal Transduction Structure Systemic Lupus Erythematosus TLR7 gene Technology Testing Therapeutic Time Tissue-Specific Gene Expression Tissues Toll-like receptors Transactivation Variant Woman Work X Inactivation cell type differential expression digital experimental study genetic corepressor genetic regulatory protein immunoregulation in vivo lupus prone mice macrophage male monocyte mutant new therapeutic target next generation non-genomic novel novel strategies novel therapeutics overexpression protective effect receptor reproductive response sex sex disparity tool transcription factor

AF2 Address Affect Age Anti-Inflammatory Agents Antigen-Antibody Complex Antiinflammatory Effect Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biological Blood Vessels Bone Marrow Cell Line Cell membrane Cell physiology Cells Chromatin DNA Binding Data Dendritic Cells Deposition Development Disease Dose End stage renal failure Environmental Exposure Epidemiology Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptors Estrogens Event Female Genes Genetic Transcription Genomics Goals Gonadal Steroid Hormones Human Immune Immune Targeting Immune response In Vitro Incidence Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Innate Immune Response Interferon Gamma Receptor Beta Chain Investigation Kidney Kidney Diseases Length Ligand Binding Domain Location Lupus Lupus Nephritis Mediating Membrane Mus Mutant Strains Mice Nephritis Nuclear Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Predisposition Property Protein Isoforms Proteins Proteinuria Puberty Race Reporting Research Risk Factors Role Sampling Selective Estrogen Receptor Modulators Serum Sex Bias Sex Chromosomes Signal Transduction Structure Systemic Lupus Erythematosus TLR7 gene Technology Testing Therapeutic Time Tissue-Specific Gene Expression Tissues Toll-like receptors Transactivation Variant Woman Work X Inactivation cell type differential expression digital experimental study genetic corepressor genetic regulatory protein immunoregulation in vivo lupus prone mice macrophage male monocyte mutant new therapeutic target next generation non-genomic novel novel strategies novel therapeutics overexpression protective effect receptor reproductive response sex sex disparity tool transcription factor

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项目摘要

Systemic lupus erythematosus (SLE) is one of many autoimmune diseases that disproportionately affects females. Although many risk factors for lupus are identified: >170 genes including GPR174, myriad environmental exposures, and aberrant X chromosome inactivation, none of these sufficiently explain the steep rise in incidence of ADs at the time of puberty in a female-specific manner. Epidemiology suggests a major role for sex hormones and their receptors in autoimmune diseases. We previously showed that female lupus-prone mice, expressing only a short form of estrogen receptor alpha (ERα short), have significantly reduced renal disease and increased survival. Determining the mechanism of this protective effect, which is estrogen dependent, is the primary goal of this proposal. Of note, ERα-/- (null) lupus prone mice were not similarly protected. Combined, our data suggest that the presence of the short form of ERα confers protection, not the absence of full-length ERα. Others and we demonstrated a critical role for ERα in dendritic cell (DC) development and endosomal Toll-like receptor (TLR) responsiveness. Interestingly, the ERα expressed in ERα short mice is similar in structure to an endogenous ERα variant (ERα46) that lacks the same AF-1 domain, and differentially regulates gene transcription compared to full length ERα. Overexpressing ERα46 in vitro also modulates TLR- induced responses, relevant to this proposal. In the proposed study, we will further investigate the role of ERα short variants in modulating TLR7-induced immune responses, and determine whether genomic and/or non- genomic mechanisms of ERα short variant action are protective. Our overall hypothesis is that increasing expression of ERα short or ERα46 in immune cells will be anti-inflammatory, and that the ratio of ERα46 to ERα66 is decreased in lupus patients versus healthy controls. We also hypothesize that targeting immune cells with novel anti-inflammatory selective estrogen receptor modulators (SERMs) that alter ERα membrane signaling and/or ERα-induced transcription will uncouple estrogen-mediated anti-inflammatory responses from those impacting reproductive tissues. We will test our hypotheses by accomplishing these Specific Aims: 1) Overexpress ERα short or treat immune cells with novel SERMs (OBHS, PaPE) that select for anti-inflammatory properties of ERα and determine the effect on known TLR7-induced inflammatory endpoints, 2) Investigate effects of membrane-only ERα signaling vs. nuclear only ERα expression on TLR7-induced pathways in mice, and 3) Identify ERα variants in human monocyte-derived dendritic cells (mo-DCs) and B cells using droplet digital PCR and Iso-Seq technology, to determine whether ERα46 is differentially expressed in lupus patients vs. controls, potentially explaining a biologic difference in females predisposed to autoimmunity. These aims will allow us to determine if we can separate ERα's reproductive effects from its potentially modifiable immune effects as a therapeutic strategy, which if successful, will provide novel approaches to immune modulation in lupus and other immune mediated diseases, especially those with a significant sex bias.

全身性红斑狼疮（SLE）是众多自身免疫性疾病之一，不成比例地影响女性。尽管发现了许多狼疮的危险因素：> 170个基因，包括GPR174，但无数环境暴露和异常的X染色体灭活，这些都没有充分解释钢青春期时广告发病率上升，以特定于女性的方式。流行病学表明主要作用性马及其在自身免疫性疾病中的接受者。我们以前表明雌性狼疮易发仅表达短形式的雌激素受体α（ERα短）的小鼠显着降低了肾脏疾病和生存增加。确定这种受保护作用的机制，即雌激素依赖是该提议的主要目标。值得注意的是，erα - / - （null）狼疮小鼠的小鼠不同受保护。合并，我们的数据表明，ERα的短形式的存在赋予保护，而不是没有全长ERα。其他人，我们证明了ERα在树突状细胞（DC）发育中的关键作用和内体电话样受体（TLR）响应能力。有趣的是，在ERα短鼠中表达的ERα是在结构上与缺乏相同AF-1结构域的内源性ERα变体（ERα46）相似，并且有差异与全长ERα相比，调节基因转录。过表达的ERα46体外还调节TLR- 诱导的响应与该提案有关。在拟议的研究中，我们将进一步研究ERα的作用调节TLR7诱导的免疫反应的简短变体，并确定基因组和/或非基因组是否 ERα短变量作用的基因组机制受到保护。我们的总体假设是增加免疫细胞中ERα短或ERα46的表达将具有抗炎作用，ERα46的比率狼疮患者与健康对照组的ERα66降低。我们还假设目标具有新型抗炎选择性雌激素受体调节剂（SERM）的免疫细胞，可改变ERα 膜信号传导和/或ERα诱导的转录将取消雌激素介导的抗炎药来自影响生殖组织的人的反应。我们将通过完成这些来检验我们的假设具体目的：1）用新的Serm（OBH，PAPE）进行过表达ERα短或治疗免疫球 ERα的抗炎特性，并确定对已知TLR7诱导的炎症终点的影响， 2）研究仅膜的ERα信号传导与仅核ERα表达对TLR7诱导的影响小鼠的途径和3）鉴定人单核细胞衍生的树突状细胞（MO-DC）和B细胞中的ERα变体使用液滴数字PCR和ISO-SEQ技术，以确定ERα46是否在狼疮患者与对照组，可能解释了易于自身免疫性的女性的生物学差异。这些目标将使我们能够确定我们是否可以将ERα的生殖效应与可能的修改分开免疫作用作为一种治疗策略，如果成功，将提供新颖的免疫方法狼疮和其他免疫介导的疾病的调节，尤其是患有重大性偏见的疾病。