Mox 1: A Novel Mitogenic Oxidase

Mox 1：一种新型有丝分裂氧化酶

• 批准号: 7811391
• 负责人: John David Lambeth
• 金额: $ 64.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811391
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult Respiratory Distress Syndrome; Affinity; Animal Model; Animals; Antioxidants; Biological; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cells; Colon Carcinoma; Cultured Cells; Data; Deoxyribonucleases; Development; Disease; Enzymes; Evaluation; Event; Fluorescence Polarization; Free Radicals; Galactosidase; Gastrointestinal tract structure; Gel; Generations; Genes; Genetic; Genetic Transcription; Goals; Grant; Growth; Human; Hypersensitivity; Inhibitory Concentration 50; Intestinal Cancer; Intestinal Neoplasms; Intestines; Knock-in Mouse; Knock-out; Knockout Mice; MAPK8 gene; MEKs; Malignant Neoplasms; Mediating; Messenger RNA; Modality; Molecular; Mus; Mutation; NADPH Oxidase; Normal tissue morphology; Oncogenic; Other Genetics; Oxidases; Oxygen; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Production; Protein Isoforms; Protein p53; Reactive Oxygen Species; Recruitment Activity; Reporter; Role; Sampling; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Source; Synthesis Chemistry; TP53 gene; Testing; Therapeutic Agents; Transcriptional Activation; angiogenesis; cancer cell; cancer type; cell growth; chromatin immunoprecipitation; deletion analysis; drug development; genetic regulatory protein; high throughput screening; improved; in vivo; inhibitor/antagonist; intestinal epithelium; mouse model; novel; novel strategies; overexpression; prevent; promoter; public health relevance; therapeutic target; tool; transcription factor; tumor; tumorigenesis; villin

DESCRIPTION (provided by applicant): The NADPH-oxidase Nox1 generates reactive oxygen species (ROS) that function through various signaling pathways to activate mitogenic growth and angiogenesis. Nox1 is overexpressed in ~ 60-70% of early human colon cancers, and considerable data point to a role in tumorigenesis. Introduction of mutationally activated K-Ras results in marked induction of Nox1 mRNA, and K-Ras-induced cell growth is prevented by antioxidants and by siRNA to Nox1. We propose that overexpression of Nox1 in human colon cancers can result from activation of Nox1 transcription by RasV12. This grant proposes to investigate the correlation of mutationally activated K-Ras and Nox1 overexpression in human tumor samples, and to investigate the signaling pathways leading to transcriptional activation of Nox1 expression. To evaluate the causal relationship between K-Ras oncogenic mutation, Nox1 overexpression, and intestinal neoplasia, Nox1 overexpressing and Nox1 knockout mice have been developed. These will also be used to test the hypothesis that Nox1 plays a causal role in intestinal tumors induced in a genetic background consisting of mutationally inactivated APC and mutationally activated K-Ras. These studies are providing proof-of-concept data for Nox1 as a therapeutic target. In a newly proposed aim, we will use medicinal chemistry approaches to improve inhibitors of Nox1 that we identified during high throughput screening of a Nox1 regulatory protein. Novel strategies are presented to improve affinity as well as isoform selectivity, so as to develop inhibitors that individually target Nox1 and Nox2. These inhibitors will be used to augment cell biological approaches in the original aims, and will also be evaluated for their potential as Nox-directed drugs. These studies will provide novel information regarding the role of Nox1 in GI cancers and may provide an important new treatment modality. PUBLIC HEALTH RELEVANCE: Free radicals that are made from oxygen have recently been found to be overproduced in several types of cancers, including those of the digestive tract. The major source of these radicals has recently been discovered to be a type of enzyme called a "Nox", and one of these, Nox1, is overproduced in colon cancer. This grant studies the way in which the gene for Nox1 is turned on to overproduce oxygen radicals and the role of these radicals as signals that cause cancer cells to divide and recruit new blood vessels. A new goal of the grant is to develop inhibitor molecules that will act on Nox1 to turn off the production of these free radicals. Such inhibitors will have potential in the treatment of several types of diseases, including cancer, cardiovascular diseases, and shock lung.

描述（由申请人提供）：NADPH氧化酶Nox 1产生活性氧（ROS），其通过各种信号传导途径发挥作用，以激活促有丝分裂生长和血管生成。Nox 1在约60-70%的早期人类结肠癌中过表达，大量数据表明其在肿瘤发生中的作用。引入突变激活的K-Ras导致Nox 1 mRNA的显著诱导，并且K-Ras诱导的细胞生长被抗氧化剂和针对Nox 1的siRNA阻止。我们提出，在人类结肠癌中Nox 1的过度表达可能是由于RasV 12激活Nox 1转录所致。该基金拟研究人类肿瘤样本中突变激活的K-Ras和Nox 1过表达的相关性，并研究导致Nox 1表达转录激活的信号通路。为了评估K-Ras致癌突变、Nox 1过表达和肠肿瘤之间的因果关系，开发了Nox 1过表达和Nox 1敲除小鼠。这些也将被用来测试的假设，即Nox 1在肠道肿瘤中起着因果作用的遗传背景下诱导的突变失活的APC和突变激活的K-Ras。这些研究为Nox 1作为治疗靶点提供了概念验证数据。在一个新提出的目标中，我们将使用药物化学方法来改善我们在Nox 1调节蛋白的高通量筛选过程中发现的Nox 1抑制剂。提出了新的策略，以提高亲和力以及异构体的选择性，从而开发抑制剂，分别针对Nox 1和Nox 2。这些抑制剂将用于增强细胞生物学方法的原始目标，也将评估其作为Nox导向药物的潜力。这些研究将提供有关Nox 1在胃肠道癌症中作用的新信息，并可能提供一种重要的新治疗方式。 公共卫生相关性：最近发现，由氧产生的自由基在几种类型的癌症中过度产生，包括消化道癌症。最近发现这些自由基的主要来源是一种称为“Nox”的酶，其中一种Nox 1在结肠癌中过量产生。该基金研究了Nox 1基因被打开以过量产生氧自由基的方式，以及这些自由基作为导致癌细胞分裂和招募新血管的信号的作用。该基金的一个新目标是开发抑制剂分子，这些分子将作用于Nox 1，以关闭这些自由基的产生。此类抑制剂将具有治疗几种类型的疾病的潜力，包括癌症、心血管疾病和休克肺。