CXCR4: A potential therapeutic target in HSK

CXCR4:HSK 的潜在治疗靶点

基本信息

  • 批准号:
    10752865
  • 负责人:
  • 金额:
    $ 38.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

Herpes stromal keratitis (HSK) is a leading cause of infection-induced vision loss in the United States. The HSK develops in response to corneal herpes simplex virus-1 (HSV-1) infection. Recurrent corneal HSV-1 infection can cause the persistence of innate immune cells, such as monocytes, neutrophils, and effector CD4 T cells in the corneal stroma of the infected cornea. As the accumulation of neutrophils and effector CD4 T cells in the HSK cornea plays a pivotal role in orchestrating the tissue damage, the strategies to manipulate the stay of infiltrating immune cells in the HSK cornea are anticipated to have an effect in reducing the HSK severity. Chemokine receptors, such as CXCR4, can play an important role in the retention of inflammatory cells in the injured tissue. CXCR4 signaling is also reported to enhance hemangiogenesis in ischemic tissue. Our preliminary results showed an increased expression of CXCR4 and CXCL12 in HSV-1 infected cornea. We recently standardized a protocol to separate an intact corneal epithelium (CE) and corneal stroma (CS) from uninfected and HSV-1 infected cornea. Single-cell suspension prepared from individual CE and CS can be used for flow cytometry. Using this strategy, we detected the presence of CXCR4-expressing cells in uninfected CE of C57BL/6 mice. Our results showed that most CXCR4-expressing cells in CE of naïve cornea display the phenotype of Langerhans cells (LCs) or plasmacytoid dendritic cells (pDCs). Recently, monoamines have been shown to engage CXCR4 on pDCs and inhibit IFN-a production. Histamine is a monoamine that is released upon corneal HSV-1 infection. Experiments proposed in aim 1 will test the hypothesis that histamine released in HSV-1 infected cornea engages CXCR4 on pDCs, and downplays IFN-a production from CE pDCs, increasing viral load. Our results also showed that the number of LCs decreases in the CE but increases in the CS from 4- day to 9-day post-infection (p.i.), suggesting a possible migration of these cells from CE to CS in HSV-1 infected corneas. An increased expression of CXCL12 (CXCR4 ligand) was detected in CS than CE of the infected cornea at 9-day p.i. Furthermore, most CD4+ T cells in the CS of infected cornea displayed effector (Ly6Chi) phenotype at 9-day p.i. Experiments proposed in aim 1 will test the hypothesis that LCs-mediated restimulation of effector CD4 T cells in the CS of the infected cornea is essential for their retention and effector function. Aim 1 experiments will also test whether LCs migrating out of CE and neutrophils infiltrating in the CE of HSV-1 infected cornea impair corneal epithelial healing. In addition to corneal resident innate immune cells, our results also detected the expression of CXCR4 on infiltrated neutrophils and vascular endothelial cells from newly formed blood vessels in the CS of HSK cornea. Experiments proposed in aim 2 will test the hypotheses that blocking CXCR4 signaling in HSK cornea will cause reverse migration of neutrophils and inhibit the development of hemangiogenesis. The successful completion of the studies proposed in this application will underscore the pleiotropic effects of CXCR4 signaling in HSK cornea and document it as a potential therapeutic target in HSK.
在美国,疱疹间质角膜炎(HSK)是感染导致视力丧失的主要原因。HSK考试

项目成果

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Susmit Suvas其他文献

Susmit Suvas的其他文献

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{{ truncateString('Susmit Suvas', 18)}}的其他基金

Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
  • 批准号:
    10468069
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
  • 批准号:
    10056782
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
  • 批准号:
    10219263
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
  • 批准号:
    10673185
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
Interplay between hypoxia and oxidative phosphorylation in herpes stromal keratitis
疱疹性基质角膜炎中缺氧与氧化磷酸化之间的相互作用
  • 批准号:
    10357859
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Interplay between hypoxia and oxidative phosphorylation in herpes stromal keratitis
疱疹性基质角膜炎中缺氧与氧化磷酸化之间的相互作用
  • 批准号:
    10586030
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
  • 批准号:
    8616376
  • 财政年份:
    2013
  • 资助金额:
    $ 38.5万
  • 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
  • 批准号:
    8504248
  • 财政年份:
    2013
  • 资助金额:
    $ 38.5万
  • 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
  • 批准号:
    9248405
  • 财政年份:
    2013
  • 资助金额:
    $ 38.5万
  • 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
  • 批准号:
    8912631
  • 财政年份:
    2013
  • 资助金额:
    $ 38.5万
  • 项目类别:

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用于癌症免疫治疗的三信号人工抗原呈递细胞
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