The Role of MTF-1 as a Mediator of Ocular Toxicity

MTF-1 作为眼毒性介质的作用

基本信息

  • 批准号:
    9014839
  • 负责人:
  • 金额:
    $ 21.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Eye pathologies, such as cataracts and macular degeneration, are the leading causes of impaired vision and blindness in the world. Although these pathologies form as a natural process of aging, there are several environmental and lifestyle factors that increase the risk of these diseases, such as cigarette smoking, exposure to light and ultraviolet radiation, oxidative stress, steroid treatment and stress-induced DNA damage. We propose to investigate the role of the metal-responsive transcription factor 1 (MTF-1) in the transcriptional regulation of a suite of genes involved in eye development that may also contribute to environmental stress- related eye pathologies. The main objectives of this proposal are to determine what role MTF-1 plays in normal eye development and whether or not inappropriate activation of MTF-1 signaling by cellular stress in the eye can lead to misexpression of genes that promote eye pathologies. Zebrafish embryos and adults will be used as our model organism and comparative experiments will be performed in a human primary lens epithelial cell line. Targeted gene expression assessments by in situ hybridization, real-time PCR and global transcriptomic profiling via RNA-seq will be used to determine the effects of MTF-1 activation or inhibition on the regulation of eye-specific genes. We have chosen the toxic metal cadmium as our model environmental risk factor because it is one of the best known activators of MTF-1 signaling and because it is believed to be a direct causative factor in the increased risk of cigarette smokers to cataractogenesis and macular degeneration. ChIP-Seq analysis complementary to the microarray expression profiling will be used to determine DNA binding by MTF- 1 as confirmation of a direct role in the regulation of genes responsible for eye development and stress-related pathologies. Additional promoter characterization via transient transfection assays and chromatin immunoprecipitation will be used for final confirmation of MTF-1 regulation of the eye-specific genes in zebrafish and humans. The results obtained from these experiments will yield public health significance by providing novel insight into mechanisms of action by which environmental stressors contribute to eye pathologies. In addition to the discovery of a potential new regulatory pathway involved in eye development with new insight into cataractogenesis and macular degeneration, successful completion of the proposed research will further expand the current use of zebrafish as a model organism for eye disease-related research.
 描述(申请人提供):眼部疾病,如白内障和黄斑变性,是世界上视力受损和失明的主要原因。虽然这些疾病是一个自然的衰老过程,但有几个环境和生活方式因素会增加这些疾病的风险,如吸烟、暴露在光线和紫外线辐射下、氧化应激、类固醇治疗和应激诱导的DNA损伤。我们建议研究金属反应转录因子1(MTF-1)在一系列涉及眼睛发育的基因转录调控中的作用,这些基因也可能与环境应激相关的眼睛病理有关。该建议的主要目的是确定MTF-1在正常眼睛发育中所起的作用,以及眼内细胞应激对MTF-1信号的不适当激活是否会导致促进眼睛病理的基因的错误表达。斑马鱼胚胎和成体将作为我们的模式生物,并将在人类原代晶状体上皮细胞系中进行比较实验。通过原位杂交、实时聚合酶链式反应和通过RNA-SEQ的全球转录图谱进行的靶向基因表达评估将用于确定MTF-1的激活或抑制对眼睛特异基因调控的影响。我们选择有毒金属镉作为我们的模型环境风险因素,因为它是MTF-1信号最著名的激活剂之一,而且被认为是吸烟者患白内障和黄斑变性风险增加的直接原因。作为微阵列表达谱分析的补充,ChIP-Seq分析将用于确定MTF-1与DNA的结合,以确认MTF-1在调控眼睛发育和压力相关病理的基因中的直接作用。通过瞬时转基因试验和染色质免疫沉淀的其他启动子特征将用于最终确认MTF-1对斑马鱼和人类眼睛特异基因的调控。从这些实验获得的结果将产生公共卫生意义,通过提供对环境应激源促进眼睛病理的作用机制的新见解。除了通过对白内障发生和黄斑变性的新见解发现与眼睛发育有关的潜在新调节途径外,拟议研究的成功完成将进一步扩大斑马鱼目前作为眼病相关研究的模式生物的用途。

项目成果

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Matthew J. Jenny其他文献

Immunological function in mice exposed to JP-8 jet fuel in utero.
子宫内暴露于 JP-8 喷气燃料的小鼠的免疫功能。
Comparative physiological, biochemical and molecular thermal stress response profiles for two unionid freshwater mussel species
两种软体淡水贻贝物种的生理、生化和分子热应激响应曲线比较
  • DOI:
    10.1242/jeb.140129
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    S. Payton;Paul D. Johnson;Matthew J. Jenny
  • 通讯作者:
    Matthew J. Jenny
Ultraviolet radiation significantly enhances the molecular response to dispersant and sweet crude oil exposure in Nematostella vectensis.
紫外线辐射显着增强了 Nematostella vectensis 对分散剂和低硫原油暴露的分子反应。
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    A. Tarrant;S. Payton;A. Reitzel;Danielle T Porter;Matthew J. Jenny
  • 通讯作者:
    Matthew J. Jenny

Matthew J. Jenny的其他文献

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{{ truncateString('Matthew J. Jenny', 18)}}的其他基金

Metal-Regulatory Factor 1 (MTF-1) Role in Development and Stress Response
金属调节因子 1 (MTF-1) 在发育和应激反应中的作用
  • 批准号:
    8116531
  • 财政年份:
    2009
  • 资助金额:
    $ 21.94万
  • 项目类别:
Metal-Regulatory Factor 1 (MTF-1) Role in Development and Stress Response
金属调节因子 1 (MTF-1) 在发育和应激反应中的作用
  • 批准号:
    7879781
  • 财政年份:
    2009
  • 资助金额:
    $ 21.94万
  • 项目类别:
Metal-Regulatory Factor 1 (MTF-1) Role in Development and Stress Response
金属调节因子 1 (MTF-1) 在发育和应激反应中的作用
  • 批准号:
    7925822
  • 财政年份:
    2009
  • 资助金额:
    $ 21.94万
  • 项目类别:
Metal-Regulatory Factor 1 (MTF-1) Role in Development and Stress Response
金属调节因子 1 (MTF-1) 在发育和应激反应中的作用
  • 批准号:
    7571754
  • 财政年份:
    2008
  • 资助金额:
    $ 21.94万
  • 项目类别:
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