Analysis of B Cell Receptor Signals Modified by Mercury

汞修饰的 B 细胞受体信号分析

基本信息

批准号：
8111865
负责人：
ALLEN J ROSENSPIRE
金额：
$ 18.81万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111865
关键词：
Address Affect Animal Model Antigens Attenuated Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Biochemical Biological Markers Bone Marrow Cell Lineage Cell surface Cells Characteristics Complex Detection Development Disease Disease susceptibility Emerging Technologies Environment Environmental Risk Factor Etiology Event Exposure to Flow Cytometry Frequencies Genetic Goals Heavy Metals Human Immune Immune Tolerance Immune system Immunogenetics Immunoglobulin M Immunomodulators Immunotoxicology Inbred BALB C Mice Individual Intervention Intoxication Intrinsic factor Knowledge Laboratories Lead Lesion Link Lymphocyte MAPK11 gene MAPK14 gene MAPK3 gene Maps Mass Spectrum Analysis Measures Mediating Mercury Multiparametric Analysis Mus Organ Output PTPRC gene Pathology Phosphoproteins Play Population Population Heterogeneity Predisposition Prevalence Process Proliferating Proteome Proteomics Publishing Receptor Signaling Receptors, Antigen, B-Cell Research Research Personnel Role Shapes Signal Pathway Signal Transduction Spleen Staging Surveys System Techniques Toxic Environmental Substances Work base central tolerance design environmental stressor human disease improved interest public health relevance receptor receptor-mediated signaling tool toxicant translational study

项目摘要

DESCRIPTION (provided by applicant): World wide the prevalence of autoimmune disease is about 3%. Autoimmune diseases can be either organ specific or systemic, but in either case their most notable quality is that their cause is multifactorial, including both genetic and environmental influences. Over the past several years much progress has been made in elucidating underlying genetic lesions associated with autoimmune disease, but surprisingly comparatively little effort has been directed towards understanding the influences of environmental factors. Our long term research goal is to correct this imbalance and further our understanding of the etiology of autoimmune disease by uncovering the mechanisms by which environmental factors, and toxicants in particular, interact with the immune system to promote autoimmune disease. A major problem in this field has been the difficulty in linking exposure to specific environmental factors, especially toxicants, with autoimmune disease. One of the few exceptions is environmental mercury. Accordingly, the focus of this proposal will be on the immunotoxicology of inorganic mercury (Hg2+). In a number of different systems Hg2+ has been shown to promote autoimmune disease. Thus Hg2+ naturally lends itself as a tool with which to probe the environment- autoimmunity axis. Recently there has been renewed interest in the role that B cells play in autoimmune diseases. Preliminary and recently published results from our laboratory support our hypothesis that low and non toxic burdens of Hg2+ < 0.01 pg/cell directly impair central tolerance in the B cell compartment by interfering with B Cell Receptor (BCR) signal transduction in immature transitional 1 (T1) B cells. Existing knowledge supports the concept that signal strength through the BCR on T1B cells is a major determinant that shapes the humoral immune repertoire and establishes tolerance to self antigens. Based on our preliminary studies, we propose that BCR signal strength is attenuated by environmentally relevant levels of Hg2+. This proposal will address the global hypothesis that BCR signaling profiles of Hg-exposed versus non-exposed B lymphocytes differ. We plan to employ flow cytometric-based techniques to map signaling networks in individual cells (i.e., single cell proteomics) as well as mass spectrometry based techniques designed to rapidly survey the B cell proteome in Hg-exposed and non-exposed cells. PUBLIC HEALTH RELEVANCE: The etiology of most autoimmune diseases is unknown, but most investigators believe that environmental and genetic factors are involved. While in recent years there has been much progress in understanding the genetic factors involved in autoimmune diseases, there has been much less progress in understanding the impact of environment. The purpose of this research is to investigate how low levels of the environmental toxicant mercury, might interact with the immune system in such a way as to promote autoimmune disease.

描述（由申请人提供）：全球自身免疫性疾病的患病率约为3％。自身免疫性疾病可以是器官特异性的，也可以是系统性的，但是在任何一种情况下，它们最著名的原因是它们的原因是多因素，包括遗传和环境影响。在过去的几年中，在阐明与自身免疫性疾病相关的潜在遗传病变方面取得了很多进展，但令人惊讶的是，为理解环境因素的影响而付出了相对较少的努力。我们的长期研究目标是纠正这种失衡，并通过发现环境因素和毒性尤其与免疫系统相互作用以促进自身免疫性疾病的机制，以进一步了解自身免疫性疾病的病因。该领域的一个主要问题是将暴露与特定环境因素（尤其是毒物）与自身免疫性疾病联系起来很难。少数例外之一是环境汞。因此，该提案的重点将放在无机汞（HG2+）的免疫毒性上。在许多不同的系统中，HG2+已显示可促进自身免疫性疾病。因此，HG2+自然将自己作为一种探测环境自身免疫轴的工具。最近，人们对B细胞在自身免疫性疾病中所起的作用引起了人们的兴趣。初步和最近发表的实验室结果支持了我们的假设，即HG2+ <0.01 pg/细胞的低和无毒负担直接通过干扰B细胞受体（BCR）信号转导不成熟的过渡1（T1）B细胞，直接损害了B细胞室中的中心耐受性。现有知识支持这样一个概念，即通过BCR对T1B细胞的强度是塑造体液免疫曲目并确立对自抗原的耐受性的主要决定因素。基于我们的初步研究，我们建议BCR信号强度受环境相关水平的HG2+衰减。该提案将解决以下全球假设：HG暴露与非暴露B淋巴细胞的BCR信号传导曲线不同。我们计划采用基于流式细胞仪的技术来绘制单个细胞（即单细胞蛋白质组学）中的信号网络以及质谱技术，旨在快速调查HG暴露和非暴露细胞中的B细胞蛋白质组。公共卫生相关性：大多数自身免疫性疾病的病因尚不清楚，但大多数研究人员认为涉及环境和遗传因素。尽管近年来，了解自身免疫性疾病所涉及的遗传因素的进展已经取得了很大进展，但了解环境的影响的进展要少得多。这项研究的目的是研究以促进自身免疫性疾病的方式与免疫系统相互作用的环境有毒物汞水平如何。