权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Mechanism Governing Oxygen Signaling and Heme Regulation by Gis1

Gis1 控制氧信号传导和血红素调节的分子机制

基本信息

批准号：
9072488
负责人：
Li Zhang
金额：
$ 4.57万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9072488
关键词：
Alzheimer&apos s Disease Amino Acids Anemia Cells Cessation of life Complex DNA DNA Binding DNA-Protein Interaction Data Disease Environment Eukaryota Event Goals Health Heme Histones Homologous Gene Human Hypoxia Hypoxia Inducible Factor In Vitro Injury Ischemia Life Liver Dysfunction Malignant Neoplasms Mediating Medical Membrane Proteins Mixed Function Oxygenases Molecular Mutagenesis Myocardial Infarction Nervous system structure Nuclear Organism Oxygen Pathogenesis Pathway interactions Porphyrias Proteins Public Health Radiation therapy Regulation Research Resistance development Science Signal Transduction Stroke Tertiary Protein Structure Testing Work Yeasts base chemotherapy design genetic regulatory protein improved innovation insight knowledge base member novel programs protein protein interaction research study response sensor tumor

项目摘要

DESCRIPTION (provided by applicant): There are fundamental gaps in understanding how regulatory proteins sense changes in oxygen and heme levels and promote cellular responses. Such gaps make it difficult to design effective strategies to treat diseases associated with hypoxia or heme dysregulation. The long- term goal is to better understand the molecular mechanisms by which the JmjC domain- containing proteins sense and promote cellular responses to changes in oxygen or heme levels. The objective of this application is to elucidate the molecular events underlying oxygen and heme regulation of Gis1 activity. The yeast Gis1 protein is a member of the JHDM3/JMJD2 subfamily of demethylases and a DNA-binding transcriptional regulator. Recent evidence shows that Gis1 is regulated by both oxygen and heme; Gis1 exemplifies a new class of regulators mediating heme and oxygen signaling. The central hypothesis is that the Gis1 JmjC domain cooperates with other domain(s) and proteins to sense and respond to changes in oxygen or heme levels and alter protein stability, protein-protein and protein-DNA interactions, thereby promoting oxygen and heme signaling. The rationale for the proposed work is that understanding how heme and oxygen regulate Gis1 can provide novel insights into how mammalian JmjC domain-containing proteins can be regulated by heme and oxygen and how their activity can be modulated to improve health. Guided by strong preliminary data, this central hypothesis will be tested by pursuing two specific aims: (1) Define the Gis1 modules mediating oxygen and heme signaling and characterize the direct interaction between Gis1 and heme; and (2) Characterize the effects of oxygen and heme on Gis1 protein interaction and DNA binding. Under the first aim, mutagenesis studies will be carried out to pinpoint Gis1 modules and residues critical for mediating oxygen and heme signaling in live cells, and in vitro studies will be carried out to examine the direct interaction between Gis1 and heme. Under the second aim, the effect of heme on Gis1 DNA binding will be examined, and purified Gis1 complexes will be characterized to determine the effect of oxygen and heme on Gis1 protein-protein interactions. The approach is innovative because it represents a new and substantive departure from the status quo in the studies of oxygen and heme signaling and of JmjC domain-containing demethylases. The proposed research is significant, because it is expected to advance the understanding of how the JmjC domain-containing proteins sense and respond to changes in oxygen and heme levels.

描述（由申请人提供）：在理解调节蛋白如何感知氧和血红素水平的变化并促进细胞反应方面存在根本性差距。这样的差距使得难以设计有效的策略来治疗与缺氧或血红素失调相关的疾病。长期目标是更好地理解含JmjC结构域的蛋白质感知和促进细胞对氧或血红素水平变化的反应的分子机制。本申请的目的是阐明Gis 1活性的氧和血红素调节的分子事件。酵母Gis 1蛋白是脱甲基酶JHDM 3/JMJD 2亚家族的成员，是一种DNA结合转录调节因子。最近的证据表明，Gis 1是由氧和血红素调节; Gis 1阐明了一类新的调节剂介导血红素和氧信号。核心假设是Gis 1 JmjC结构域与其他结构域和蛋白质合作，以感知和响应氧或血红素水平的变化，并改变蛋白质稳定性、蛋白质-蛋白质和蛋白质-DNA相互作用，从而促进氧和血红素信号传导。这项工作的基本原理是，了解血红素和氧如何调节Gis 1可以为哺乳动物含JmjC结构域的蛋白质如何受到血红素和氧的调节以及如何调节它们的活性以改善健康提供新的见解。在强有力的初步数据的指导下，这一中心假设将通过追求两个具体目标进行测试：（1）定义介导氧和血红素信号传导的Gis 1模块，并表征Gis 1和血红素之间的直接相互作用;（2）表征氧和血红素对Gis 1蛋白相互作用和DNA结合的影响。在第一个目标下，将进行诱变研究，以确定对介导活细胞中的氧和血红素信号传导至关重要的Gis 1模块和残基，并将进行体外研究，以检查直接相互作用 Gis 1和血红素之间的关系在第二个目标下，血红素对Gis 1 DNA结合的影响将被检查，纯化的Gis 1复合物将被表征以确定氧和血红素对Gis 1蛋白质-蛋白质相互作用的影响。这种方法是创新的，因为它代表了一个新的和实质性的偏离现状的研究氧和血红素信号和JmjC结构域含有脱甲基酶。这项研究意义重大，因为它有望促进对含JmjC结构域的蛋白质如何感知和响应氧和血红素水平变化的理解。