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ENDOTOXIN AND SUSCEPTIBILITY TO TRICHOTHECENE MYCOTOXINS

内毒素和对单端孢霉烯真菌毒素的敏感性

基本信息

批准号：
6518132
负责人：
James J Pestka
金额：
$ 19.17万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2004-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6518132
关键词：
apoptosis bacterial toxicology bacterial toxins chemical structure function corticosterone dosage gene expression genetic susceptibility host organism interaction laboratory mouse lipopolysaccharides lymphatic disorder lymphocyte mycotoxins phenotype prostaglandin E tumor necrosis factor alpha

项目摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) "There is increasing evidence that human exposure to bacterial endotoxin (lipopolysaccharide, LPS) is common and that LPS exposure may increase the susceptibility of individuals to tissue injury by a variety of chemical agents. In this proposal, the investigators seek to examine this paradigm by determining the mechanisms by which LPS and one class of immunotoxicants, the trichothecene mycotoxins, interact to cause depletion of lymphoid tissue. Trichothecenes are food and indoor air contaminants that include some of the most potent protein synthesis inhibitors known. The investigators have observed that, following co-exposure of mice to small doses of LPS and the trichothecene vomitoxin (VT), mRNA expression and serum concentrations of TNF-alpha are greatly elevated as compared to mice receiving LPS or VT alone. Subsequently, apoptosis in lymphoid tissue is observed as the earliest and most prominent histologic lesion. The investigators hypothesize that induction of lymphocyte apoptosis by LPS and trichothecene co-exposure is mediated by elevated TNF-alpha expression and TNF-alpha mediated sequelae. To test this hypothesis, the investigators propose to achieve three Specific Aims in a murine model. In Aim 1, we will characterize and measure lymphocyte apoptosis following exposure to LPS and VT in vivo with respect to dose, timing and susceptible phenotypes. In Aim 2, the investigators will relate elevated expression of TNF-alpha and TNF- alpha mediated sequelae (i.e. corticosterone, prostaglandin E2 [PG E2]) to lymphocyte apoptosis that occurs following exposure to LPS and VT in vivo. In Aim 3, the investigators will determine the extent to which in vitro exposure to VT can directly induce apoptosis or augment the action of TNF-alpha, corticosterone, PGE2, and other apogenic signals in selected lymphocyte phenotypes. Structure-activity relationships among common trichothecenes encountered by humans will be examined using relevant Aim 1 and 3 endpoints. The immediate outcomes of this project will improve mechanistic understanding of how LPS and trichothecens interacts to cause lymphocyte death and the role of TNF-alpha in the process. Over the long term, this research will provide insight into adverse immunologic consequences that may occur in LPS-exposed individuals who are exposed to environmental toxicants."

产品说明：（改编自研究者摘要）“越来越多的证据表明，人体暴露于细菌内毒素（脂多糖，LPS）是常见的，LPS暴露可能会增加个体对各种化学试剂造成的组织损伤的易感性。在这项提议中，研究人员试图通过确定LPS和一类免疫毒素（即二孢霉烯真菌毒素）相互作用导致淋巴组织耗竭的机制来研究这种范式。单端孢霉烯是食物和室内空气污染物，包括一些已知的最有效的蛋白质合成抑制剂。研究人员已经观察到，在将小鼠共同暴露于小剂量的LPS和喜树碱呕吐毒素（VT）之后，与单独接受LPS或VT的小鼠相比，TNF-α的mRNA表达和血清浓度大大升高。随后，淋巴组织中的细胞凋亡作为最早和最显著的组织学病变被观察到。研究者假设LPS和二苯乙烯共同暴露诱导淋巴细胞凋亡是由TNF-α表达升高和TNF-α介导的后遗症介导的。为了验证这一假设，研究人员提出在小鼠模型中实现三个特定目标。在目标1中，我们将描述和测量淋巴细胞凋亡后暴露于LPS和VT在体内的剂量，时间和易感表型。在目标2中，研究者将TNF-α和TNF-α介导的后遗症（即皮质酮、前列腺素E2 [PG E2]）的表达升高与体内暴露于LPS和VT后发生的淋巴细胞凋亡相关。在目标3中，研究者将确定体外暴露于VT可直接诱导细胞凋亡或增强TNF-α、皮质酮、PGE 2和其他脱辅基信号在选定淋巴细胞表型中的作用的程度。将使用相关的目标1和3终点来检查人类遇到的常见的多烯类化合物之间的结构-活性关系。该项目的直接结果将提高对LPS和大肠杆菌如何相互作用导致淋巴细胞死亡以及TNF-α在该过程中的作用的机械理解。从长远来看，这项研究将提供深入了解可能发生在暴露于环境毒物的LPS暴露个体中的不良免疫学后果。"