Mox 1: A Novel Mitogenic Oxidase

Mox 1：一种新型有丝分裂氧化酶

基本信息

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
项目类别：
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

项目摘要

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 Nox1 产生活性氧 (ROS)，其通过各种信号传导途径发挥作用，激活有丝分裂生长和血管生成。 Nox1 在约 60-70% 的早期人类结肠癌中过度表达，大量数据表明 Nox1 在肿瘤发生中发挥作用。引入突变激活的 K-Ras 会导致 Nox1 mRNA 的显着诱导，并且抗氧化剂和 Nox1 的 siRNA 可以阻止 K-Ras 诱导的细胞生长。我们认为，Nox1 在人类结肠癌中的过度表达可能是 RasV12 激活 Nox1 转录的结果。该资助计划研究人类肿瘤样本中突变激活的 K-Ras 和 Nox1 过表达的相关性，并研究导致 Nox1 表达转录激活的信号通路。为了评估 K-Ras 致癌突变、Nox1 过度表达和肠肿瘤之间的因果关系，我们培育了 Nox1 过度表达和 Nox1 敲除小鼠。这些也将用于检验这样的假设：Nox1 在由突变失活的 APC 和突变激活的 K-Ras 组成的遗传背景下诱导的肠道肿瘤中发挥因果作用。这些研究为 Nox1 作为治疗靶点提供了概念验证数据。在新提出的目标中，我们将使用药物化学方法来改进我们在 Nox1 调节蛋白高通量筛选过程中发现的 Nox1 抑制剂。提出了提高亲和力和亚型选择性的新策略，从而开发单独靶向 Nox1 和 Nox2 的抑制剂。这些抑制剂将用于增强细胞生物学方法的最初目标，并且还将评估其作为 Nox 导向药物的潜力。这些研究将提供有关 Nox1 在胃肠道癌症中的作用的新信息，并可能提供一种重要的新治疗方式。公共健康相关性：最近发现，由氧气产生的自由基在多种类型的癌症中过量产生，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，其中之一，Nox1，在结肠癌中过量产生。这笔资助研究了 Nox1 基因被开启以过度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。该资助的一个新目标是开发能够作用于 Nox1 的抑制剂分子，以阻止这些自由基的产生。此类抑制剂将具有治疗多种疾病的潜力，包括癌症、心血管疾病和休克性肺病。