Stress Signaling Pathways in Toxicity and Disease

毒性和疾病中的应激信号通路

基本信息

批准号：
8116697
负责人：
Michael Karin
金额：
$ 33.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-06-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116697
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Adaptor Signaling Protein Affect Alleles Amino Acids Applications Grants Area Asthma Biochemical Biochemistry Caspase Caspase-1 Cells Chronic Chronic Disease Colon Crohn&apos s disease Development Dietary Fats Diethylnitrosamine Disease Dust Environmental Risk Factor Excision Exhibits Experimental Pathology Exposure to Fibrosis Frameshift Mutation Genetic Genetic Predisposition to Disease Grant Hepatocyte Hepatotoxicity Hyperlipidemia Hypersensitivity Immune response In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Injury Insulin Resistance Interleukin-6 Isoenzymes Lead Leucine-Rich Repeat Ligands Link Lipids Liver Liver diseases MAP Kinase Modules MAPK14 gene MAPK8 gene Malignant Neoplasms Malignant neoplasm of liver Mediating Mediator of activation protein Modeling Molecular Molecular Genetics Mus Mutant Strains Mice N-terminal NF-kappa B Non-Insulin-Dependent Diabetes Mellitus Normal Cell Obesity Palmitic Acids Pancreas Pathogenesis Pathway interactions Pattern Pattern recognition receptor Play Predisposition Procedures Process Production Protein Isoforms Protein Kinase Protein Kinase C Receptor Signaling Research Research Personnel Role Saturated Fatty Acids Signal Pathway Signal Transduction Site Smoke Stimulus Stress Syndrome Testing Tobacco smoke Toll-like receptors Toxic Environmental Substances Toxic effect Toxin Transducers United States National Institutes of Health Unsaturated Fatty Acids Wild Type Mouse absorption airway inflammation base cytokine hepatotoxin interest macrophage microbial mitogen-activated protein kinase p38 mouse model mutant oxidized lipid pathogen programs receptor research study response sensor stress activated protein kinase toxicant tumor

项目摘要

DESCRIPTION (provided by applicant): We propose that pattern recognition receptors, whose normal function is in innate immune responses, are also activated by stress-generated ligands, such as molecules released by dying cells, normal and oxidized lipids and a variety of so called "danger" signals in addition to environmental toxins and pathogen associated molecular patterns. Activation of such receptors either by endogenous- (i.e. host-generated) or pathogen- generated ligands turns on stress-activated protein kinases, such as JNK, p38 MAPK and IKK, that serve as molecular transducers that contribute to development of chronic inflammatory diseases. Importantly, these pathogenic mechanisms allow the integration of environmental factors and genetic susceptibility loci that together contribute to the development of some of the most common chronic diseases, including type 2 diabetes, asthma, inflammatory bowel disease and chronic liver disease. In the previous grant period we have generated strong evidence in support of this hypothesis by focusing on the pathogenic functions of the JNK and IKK signaling pathways. We also generated a mouse model expressing the equivalent of the most common susceptibility allele for Crohn's disease, an inflammatory bowl disease whose pathogenesis is affected by genetic and environmental factors. In the present period we will focus our main effort on the pathogenic function of different classes of pattern recognition receptors as targets for stress - and injury- generated stimuli, as well as continue with our studies on the role of p38 MAPK in liver inflammation and toxicity. More specifically we will examine: 1) the role of protein kinase C isozymes and Toll like receptors (TLRs) in obesity-induced JNK activation and insulin resistance; 2) the role of TLRs in toxin-induced liver injury, liver inflammation and liver cancer; 3) examine the role of p38 MAPK in toxin-induced liver injury, liver inflammation and liver cancer; 4) examine the mechanism by which the intracellular NOD-like receptor NOD2 leads to activation of caspase 1 and IL-lbeta secretion; 5) construct a conditional mouse mutant that allows constitutive NOD2 activation and use it along with our previously generated Nod2delta33 knockin mutant to examine effects of tobacco smoke, microparticles and bacterial products on development of NOD2- modulated colonic and airway inflammation. To accomplish these aims we will use a combination of cellular biochemistry, molecular genetics and experimental pathology, an approach that has been proven effective during the previous project period.

描述（由申请人提供）：我们提出，正常功能在先天免疫反应中的模式识别受体也被压力生成的配体激活，例如由垂死细胞释放的分子，正常和氧化的脂质以及各种所谓的“危险”信号，此外还具有环境毒素和病原体相关的分子模式。通过内源性（即宿主产生的）或病原体配体激活这种受体，将触发性激活的蛋白激酶（例如JNK，p38 MAPK和IKK）作为分子传感器，这些激酶有助于慢性炎症性疾病的发育。重要的是，这些致病机制允许整合环境因素和遗传易感性基因座，共同有助于发展一些最常见的慢性疾病，包括2型糖尿病，哮喘，炎症性肠病和慢性肝病。在上一个赠款期间，我们通过着重于JNK和IKK信号通路的致病功能来产生强大的证据来支持这一假设。我们还产生了一个小鼠模型，表达了克罗恩病最常见的易感性等位基因，这是一种炎症碗疾病，其发病机理受遗传和环境因素的影响。在目前，我们将主要的努力集中在不同类别的模式识别受体的致病功能上，作为压力和损伤产生的刺激的靶标，并继续研究p38 MAPK在肝脏炎症和毒性中的作用。更具体地说，我们将研究：1）蛋白激酶C同工酶和类似受体（TLR）在肥胖引起的JNK激活和胰岛素抵抗中的作用； 2）TLR在毒素诱导的肝损伤，肝炎和肝癌中的作用； 3）检查p38 MAPK在毒素诱导的肝损伤，肝炎和肝癌中的作用； 4）检查细胞内NOD样受体NOD2导致caspase 1和IL-LBETA分泌激活的机制； 5）构建一种有条件的小鼠突变体，该突变体允许构成NOD2激活，并将其与我们先前生成的NOD2DELTA33敲蛋白突变体一起使用，以检查烟草烟雾，微粒和细菌产品对NOD2调节结肠和气道炎症的发展的影响。为了实现这些目标，我们将使用细胞生物化学，分子遗传学和实验病理学的结合，这种方法已被证明在上一个项目时期有效。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.

DOI：
10.1016/j.ccr.2008.06.016
发表时间：
2008-08-12
期刊：
Cancer cell
影响因子：
50.3
作者：
Sakurai T;He G;Matsuzawa A;Yu GY;Maeda S;Hardiman G;Karin M
通讯作者：
Karin M

Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis.

DOI：
10.1038/nature07623
发表时间：
2009-01-01
期刊：
NATURE
影响因子：
64.8
作者：
Kim, Sunhwa;Takahashi, Hiroyuki;Lin, Wan-Wan;Descargues, Pascal;Grivennikov, Sergei;Kim, Youngjun;Luo, Jun-Li;Karin, Michael
通讯作者：
Karin, Michael

Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6.

DOI：
10.1002/art.34489
发表时间：
2012-09
期刊：
ARTHRITIS AND RHEUMATISM
影响因子：
0
作者：
Guma, Monica;Hammaker, Deepa;Topolewski, Katharyn;Corr, Maripat;Boyle, David L.;Karin, Michael;Firestein, Gary S.
通讯作者：
Firestein, Gary S.

Is NF-kappaB the sensor of oxidative stress?