INFLAMMATORY RESPONSES IN THE TOXICITY OF RICIN

蓖麻毒素毒性的炎症反应

基本信息

批准号：
7232352
负责人：
BRUCE E. MAGUN
金额：
$ 35.79万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-15 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232352
关键词：
Abrin Acute Adenine Adhesions Affect Animals Apical Apoptosis Apoptosis Promoter Apoptotic Appearance Attention Bacteria Caspase Inhibitor Cell Death Cell membrane Cells Cessation of life Clinical Condition Cultured Cells Depurination Development Disease E-Selectin Employment Endothelial Cells Escherichia coli Event Exhibits Experimental Animal Model Family Gene Activation Gene Silencing Genes Genetic Genetic Engineering Genetic Transcription Germ Cells Health Hemolysis Hemolytic-Uremic Syndrome Histocompatibility Testing Homologous Protein Human Infiltration Inflammation Inflammatory Inflammatory Response Inhibition of Apoptosis Interleukin-1 Intoxication Kidney Kidney Failure Knock-out Knockout Mice Laboratories Lead Lesion Leukocytes Ligands Lung MAP Kinase Gene MAPK14 gene MAPK8 gene Measures Mediating Mediator of activation protein Messenger RNA Methods Mitochondria Modeling Molecular Mus Numbers Oligonucleotide Microarrays Organ Organism Passive Immunization Pathology Pathway interactions Phosphotransferases Pisum sativum Plants Play Poisoning Population Precatory Bean Plant Predisposition Primer Extension Protein Inhibition Protein Synthesis Inhibition RNA, Ribosomal, 28S Rattus Recombinants Resistance Ribosomes Ricin Risk Role Seeds Serum Shiga Toxin Signal Transduction Stem cells Target Populations Thinking Thrombocytopenia Tissues Toxic effect Toxin Transcriptional Activation Translations Tumor Necrosis Factor Receptor Ursidae Family Vascular System Viral caspase-8 caspase-9 cell type chemokine cytochrome c cytokine cytotoxic extracellular improved in vivo kidney cell laser capture microdissection macrophage member mouse model response stem stress activated protein kinase transcription factor

项目摘要

DESCRIPTION (provided by applicant): In view of its wide availability and ease of purification, ricin has been employed as a toxic and lethal agent by totalitarian regimes and, recently, by terrorist groups. Ricin is a member of a family of ribosome-directed toxins whose toxicity stems from the depurination of a single adenine within the "sarcin/ricin" loop of 28S ribosomal RNA (28S rRNA). The depurination of 28S rRNA results not only in the inhibition of protein translation, but also the intense and extended activation of the stress-activated protein kinases such as JNK and p38 MAPK. These kinases are thought to be central mediators of inflammatory responses that are responsible for inducing the transcription of proinflammatory cytokines and chemokines. The development of interventional remedies in cases of poisoning by ricin and other ribosome-directed toxins will depend critically on our improved understanding of the primary target tissues affected and the mechanisms that drive the proinflammatory and cytotoxic responses. When administered to cultured cells or to mice, ricin potently induces the activation of genes that encode proinflammatory cytokines and chemokines and the transcription factors that are known to drive their expression. Simultaneously, ricin activates apoptotic pathways, via engagement of apical caspases 8 and 9, which lead to cell death. Our preliminary studies support the notion that the health risks that accompany ricin intoxication stem from ricin' s activation of inflammatory and apoptotic pathways. In this application we propose to employ ricin in both cultured cells and in wild-type and "knockout" mice to elucidate the initial targets of action, the cytotoxic consequences, and the cellular and molecular mechanisms that are pursuant to intoxication by ricin. In this application we propose to: 1) identify target tissues and cell types affected by ricin in a mouse model of ricin intoxication; 2) identify genes whose expression is induced by ricin in specific cell and tissue types; 3) determine the mechanisms of apoptosis triggered by ricin and the roles of apoptosis in the course of ricin-induced inflammation; and 4) elucidate the roles of specific inflammatory or pro-apoptotic genes in mediating the response to ricin intoxication by employing mouse "knock out" models.

描述（由申请人提供）：鉴于其广泛使用且易于纯化，蓖麻毒素已被极权主义政权以及最近的恐怖组织用作有毒和致命剂。蓖麻毒素是核糖体定向毒素家族的一员，其毒性源于 28S 核糖体 RNA (28S rRNA) 的“蓖麻毒素/蓖麻毒素”环内单个腺嘌呤的脱嘌呤。 28S rRNA 的脱嘌呤不仅会抑制蛋白质翻译，还会导致应激激活蛋白激酶（如 JNK 和 p38 MAPK）的强烈和长期激活。这些激酶被认为是炎症反应的中心介质，负责诱导促炎细胞因子和趋化因子的转录。在蓖麻毒素和其他核糖体导向毒素中毒的情况下，介入疗法的开发将主要取决于我们对受影响的主要靶组织以及驱动促炎和细胞毒性反应的机制的进一步了解。当给予培养细胞或小鼠时，蓖麻毒素可有效诱导编码促炎细胞因子和趋化因子的基因以及已知驱动其表达的转录因子的激活。同时，蓖麻毒素通过顶端半胱天冬酶 8 和 9 的参与激活细胞凋亡途径，从而导致细胞死亡。我们的初步研究支持这样的观点，即伴随蓖麻毒素中毒的健康风险源于蓖麻毒素激活炎症和细胞凋亡途径。在本申请中，我们建议在培养细胞以及野生型和“基因敲除”小鼠中使用蓖麻毒素来阐明作用的初始目标、细胞毒性后果以及蓖麻毒素中毒的细胞和分子机制。在本申请中，我们建议：1）在蓖麻毒素中毒小鼠模型中鉴定受蓖麻毒素影响的靶组织和细胞类型； 2) 鉴定在特定细胞和组织类型中由蓖麻毒素诱导表达的基因； 3）确定蓖麻毒素引发细胞凋亡的机制以及细胞凋亡在蓖麻毒素诱导的炎症过程中的作用； 4) 通过使用小鼠“敲除”模型，阐明特定炎症或促凋亡基因在介导蓖麻毒素中毒反应中的作用。