An Oxygen-Sensing Network Involving Heme and Chaperones

涉及血红素和伴侣的氧传感网络

基本信息

批准号：
7901855
负责人：
Li Zhang
金额：
$ 13.56万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-31 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7901855
关键词：
Anemia Animal Model Binding Biochemical Biochemical Genetics Biological Biological Models Biological Process Cell Cycle Cell physiology Characteristics Cobalt Complex Computational algorithm Copper DNA Databases Defect Disease Drug Metabolic Detoxication Electron Transport Elements Erythropoiesis Eukaryota Event Figs - dietary Funding Gene Expression Microarray Analysis Gene Expression Regulation Genes Genetic Genetic Transcription Goals Health Hematological Disease Heme Human Investigation Ischemia Knowledge Life Link Literature Lung diseases Malignant Neoplasms Mammals Mediating Metabolism Microarray Analysis Molecular Molecular Chaperones Organism Oxidative Phosphorylation Oxygen Pathologic Processes Physiological Play Porphyrias Process Production Proteins Regulation Repression Research Role Saccharomyces cerevisiae Signal Transduction Testing Transcription Coactivator Transcriptional Activation Transcriptional Regulation Work Yeasts angiogenesis citral B gene repression improved neurogenesis novel oxidation oxidative damage research study respiratory response sensor

项目摘要

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to elucidate the molecular mechanisms governing oxygen sensing, heme signaling and chaperone action in eukaryotes. Oxygen is vital for maintaining critical cellular functions in many living organisms, and heme is central to oxygen sensing and utilization. In humans, defects in oxygen sensing and regulation or in heme synthesis cause serious diseases in humans, including cancers, porphyrias, and respiratory and hematological diseases. Thus, understanding how oxygen is sensed and how heme and molecular chaperones promote oxygen and global gene regulation is important for improving human health. This proposal uses yeast as a model system for investigating oxygen sensing, heme signaling and chaperone action in eukaryotes. In yeast, heme mediates oxygen regulation of many genes by controlling the transcriptional activity of the heme activator protein Hapl. Molecular chaperones Hsp90 and Hsp70 bind to Hapl and promote heme regulation of Hapl activity. Experiments in this proposal will rigorously test the following hypotheses: (1) Hapl-multichaperone complexes bind directly to DNA and promote transcriptional aactivation and repression; (2) the oxygen level is sensed through heme synthesis; and (3) heme and Hapl play key roles in global oxygen sensing and global transcription regulation. The specific aims are (1) to clarify and compare the molecular mechanisms by which Hapl activates and represses transcription, (2) to dissect the molecular mechanism by which intracellular heme level is linked to oxygen level, and (3) to determine the global roles of heme and Hapl in oxygen sensing and regulation. Biochemical, genetic, and advanced microarray technologies and computational algorithms will be used to accomplish these aims. The gained knowledge should facilitate the understanding of the molecular mechanisms of oxygen sensing, heme signaling and chaperone action in higher eukaryotes.

描述（由申请人提供）：该提案的广泛，长期目标是阐明真核生物中控制氧气感应，血红素信号传导和伴侣蛋白作用的分子机制。氧气对于在许多生物体中保持关键细胞功能至关重要，而血红素对于氧气感应和利用至关重要。在人类中，氧气传感和调节或血红素合成中的缺陷会导致人类严重疾病，包括癌症，卟啉症以及呼吸道和血液学疾病。因此，了解如何感测氧，以及血红素和分子伴侣如何促进氧气和全球基因调节对于改善人类健康至关重要。该建议使用酵母作为模型系统，用于研究真核生物中的氧气传感，血红素信号传导和伴侣作用。在酵母中，血红素通过控制血红素激活蛋白HAPL的转录活性来介导许多基因的氧气调节。分子伴侣HSP90和HSP70结合单位，并促进Heme调节单位活性。该提案中的实验将严格检验以下假设：（1）Hapl-Multichaperone复合物直接与DNA结合，并促进转录激活和抑制；（2）通过血红素合成来感测氧；（3）血红素和HAPL在全球氧气传感和全球转录调控中起关键作用。具体目的是（1）澄清和比较单个单位激活和抑制转录的分子机制，（2）剖定细胞内血红素水平与氧水平相关的分子机制，（3）确定血红素和单位在氧气感应和调节中的全球作用。生化，遗传和先进的微阵列技术和计算算法将用于实现这些目标。所获得的知识应促进对较高真核生物中氧气传感，血红素信号传导和伴侣作用的分子机制的理解。