COMBINATORIAL CONTROL OF TOXIN RESPONSE IN C ELEGANS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 环境中的化学物质，包括污染物、处方药和膳食成分，通过改变许多细胞类型的生化组成，对人体的生理机能产生巨大影响。这些外来化合物，统称为外源性物质，通过诱导基因表达调控的变化来改变细胞中存在的一系列酶。这种诱导的中心参与者是所谓的"异生物质感应"受体，其是配体调节的转录因子的核受体（NR）超家族的成员。NR的NR 1亚家族的成员直接将毒素的存在与负责异生物质解毒和外排的I相和II相代谢酶和药物转运蛋白的产生联系起来。这些NR的结构，具有配体和DNA结合域，反映了它们的功能：异生物质结合，受体易位，和靶基因转录激活。然而，越来越多的证据表明，异种感觉的分子途径很难这么简单。异种感知NR、介导其他信号传导事件的NR、甚至非NR转录调节因子之间的串扰证明了异种感知与其他生理学如脂质和碳水化合物代谢以及激素信号传导的交叉。生物化学去除环境污染物和化学治疗剂如何影响细胞的正常生物化学？反过来，正常的细胞生物化学如何影响外源性物质的清除？我们建议，组合控制的解毒NR大大拓宽了已知的生物学这些重要的化学传感器。要充分了解药物和环境污染物如何影响人类健康，就必须完全了解生物外源性解毒和其他细胞生物化学之间的联系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chemicals in the environment, including pollutants, prescription drugs, and dietary ingredients have a dramatic effect on the physiology of the body by changing the biochemical makeup of many cell types. These foreign compounds, collectively called xenobiotics, alter the suite of enzymes present in cells through induced changes in the regulation of gene expression. Central players in this induction are the so-called "xenobiotic-sensing" receptors which are members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors. Members of the NR1 subfamily of NRs directly link the presence of toxins to the production of phase I and II metabolizing enzymes and drug transporters responsible for xenobiotic detoxification and efflux. The structure of these NRs, possessing both ligand and DNA binding domains, reflects their function: xenobiotic binding, receptor translocation, and target gene transcriptional activation. Yet, increasing evidence suggests that the molecular pathway of xenosensation is hardly this simple. Crosstalk between xenosensing NRs, NRs mediating other signaling events, and even non-NR transcriptional regulators demonstrates the intersection of xenosensation with other physiologies such as lipid and carbohydrate metabolism and hormonal signaling. How does the biochemical removal environmental contaminants and chemotherapeutic agents impact the normal biochemistry of cells? Reciprocally, how does normal cellular biochemistry impact the clearance of xenobiotics? We propose that the combinatorial control of detoxification by NRs greatly broadens the known biology of these important chemical sensors. A complete understanding of the connections between xenobiotic detoxification and other cellular biochemistry is required to fully understand how drugs and environmental contaminants impact human health.