Identifying the molecular target for macrophage activation by chlorpyrifos

确定毒死蜱激活巨噬细胞的分子靶标

基本信息

  • 批准号:
    10555298
  • 负责人:
  • 金额:
    $ 19.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-25 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

Chronic exposure to low levels of organophosphate pesticides is associated with increased risk for asthma. We have shown in experimental animals that low-level exposure activates lung macrophages to produce TNFa, which in turn decreases expression and function of inhibitory M2 muscarinic receptors on airway parasympathetic nerves, increasing the release of acetylcholine and potentiating reflex bronchoconstriction. We hypothesize that molecular targets responsible for activation of macrophages by organophosphates can be identified. To do so, we propose two specific aims: Specific Aim #1: Use photocrosslinking and click chemistry to identify potential targets that chlorpyrifos binds to on macrophages. We will synthesize chlorpyrifos photoaffinity ligand derivatives, and use these to identify proteins in THP-1 macrophages that chlorpyrifos binds to. By competition with unmodified chlorpyrifos, we will identify targets of specific binding by chlorpyrifos. We will also use CRISPR Cas9 gene editing to eliminate the protein target in THP-1 cells, and test whether this prevents chlorpyrifos binding and activation by chlorpyrifos. Results will be confirmed in experiments using human lung macrophages obtained by digestion of whole lungs. Specific Aim #2: Use genome-wide CRISPR Cas9 gene editing to eliminate proteins in THP-1 cells, testing the ability of deletions to block activation of THP-1 macrophages by chlorpyrifos. This approach will be complementary to the photocrosslinking approach in Specific Aim #1, in that it will identify both chlorpyrifos- binding proteins and also other proteins involved in signal transduction of chlorpyrifos activation. Comparing results with binding data in Specific Aim #1 will differentiate among these groups of protein targets. We will also test whether deleting the chlorpyrifos target protein decreases macrophage activation by the structurally related organophosphates diazinon and parathion, which also cause hyperreactivity by activating macrophages. These results will be confirmed in experiments using human lung macrophages obtained by digestion of whole lungs. At the completion of this project, we will have identified the molecular target responsible for macrophage activation by chlorpyrifos. Understanding this mechanism will suggest new therapeutic targets in pesticide induced asthma. It will also be relevant to the central nervous system effects of low-level organophosphate exposure, which are associated with activation of microglia, the resident macrophages of the brain. We will also have established a new method for investigating interactions of organophosphates with target cells, which will have broad applicability in studying the health effects of these ubiquitous environmental contaminants.
长期接触低水平的有机磷农药会增加患哮喘的风险。我们

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Michael S Cohen其他文献

The significance of mast cells in basal cell carcinoma.
肥大细胞在基底细胞癌中的意义。
NON-CLAMPED, NON-ISCHEMIC PARTIAL NEPHRECTOMY: THE NEW GOLD STANDARD
  • DOI:
    10.1016/s0022-5347(08)61400-7
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Teodora Kurteva;Michael S Cohen;Gjanje L Smith;John A Libertino
  • 通讯作者:
    John A Libertino
THE QUEST TO FIND HIGH GRADE PROSTATE CANCER: ARE WE FAILING?
  • DOI:
    10.1016/s0022-5347(08)60430-9
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sarah Fitch;Michael S Cohen;Robin Ruthazer;John A Libertino
  • 通讯作者:
    John A Libertino
AI Model Versus Clinician Otoscopy in the Operative Setting for Otitis Media Diagnosis.
AI 模型与临床医生耳镜检查在中耳炎诊断手术中的比较。
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Krish Suresh;Michael P Wu;Fouzi Benboujja;Barbara Christakis;Alice Newton;Christopher J. Hartnick;Michael S Cohen
  • 通讯作者:
    Michael S Cohen
Reward enhancement of item-location associative memory spreads to similar items within a category.
项目位置关联记忆的奖励增强会扩散到类别内的相似项目。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    2.6
  • 作者:
    Evan Grandoit;Michael S Cohen;Paul J. Reber
  • 通讯作者:
    Paul J. Reber

Michael S Cohen的其他文献

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{{ truncateString('Michael S Cohen', 18)}}的其他基金

Identifying the targets of virus-induced PARPs during SARS-CoV-2 infection
识别 SARS-CoV-2 感染期间病毒诱导的 PARP 的靶标
  • 批准号:
    10573499
  • 财政年份:
    2022
  • 资助金额:
    $ 19.25万
  • 项目类别:
Identifying the molecular target for macrophage activation by chlorpyrifos
确定毒死蜱激活巨噬细胞的分子靶标
  • 批准号:
    10467360
  • 财政年份:
    2022
  • 资助金额:
    $ 19.25万
  • 项目类别:
Decoding protein MARylation networks in astrocytes using chemical biology approaches
使用化学生物学方法解码星形胶质细胞中的蛋白质 MARylation 网络
  • 批准号:
    10599222
  • 财政年份:
    2014
  • 资助金额:
    $ 19.25万
  • 项目类别:
Decoding protein ADP-ribosylation networks in neurons using a chemical genetic ap
使用化学遗传 ap 解码神经元中的蛋白质 ADP-核糖基化网络
  • 批准号:
    9272745
  • 财政年份:
    2014
  • 资助金额:
    $ 19.25万
  • 项目类别:
Decoding protein ADP-ribosylation networks in neurons using a chemical genetic ap
使用化学遗传 ap 解码神经元中的蛋白质 ADP-核糖基化网络
  • 批准号:
    8765046
  • 财政年份:
    2014
  • 资助金额:
    $ 19.25万
  • 项目类别:
Decoding protein MARylation networks in astrocytes using chemical biology approaches
使用化学生物学方法解码星形胶质细胞中的蛋白质 MARylation 网络
  • 批准号:
    10378049
  • 财政年份:
    2014
  • 资助金额:
    $ 19.25万
  • 项目类别:

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脱细胞小直径动脉移植物的研制及大动物实验评价
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  • 批准号:
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从未复制过成功的实验?
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