Wnt5a, a New Diabetic Corneal Marker Related to Wound Healing

Wnt5a,一种与伤口愈合相关的新糖尿病角膜标记物

基本信息

  • 批准号:
    10682429
  • 负责人:
  • 金额:
    $ 41.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-30 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Diabetes is the most widespread blinding disease in working-age adults. Up to 70% of diabetic patients suffer from corneal problems including neuropathy and epithelial keratopathy (impaired wound healing, ulcers, recurrent erosions) that impair vision and cause pain and discomfort. Diabetic keratopathy is underdiagnosed, and therapy remains symptomatic. We previously identified markers altered in human diabetic corneas and normalized their levels in human corneal organ cultures by gene and nano therapy, which also restored normal stem cell phenotype and corneal wound healing. Epigenetic changes may contribute to diabetic complications. Therefore, we examined epigenetic DNA methylation in human diabetic corneas and found a set of genes abnormally methylated vs. normal corneas. WNT5A gene, a noncanonical member of Wnt regulators of cell motility, proliferation and differentiation, was hypermethylated in diabetic corneas. Its expression was reduced in diabetic corneas and stem cell-enriched epithelial cultures. Wnt5a addition accelerated wound healing in diabetic (but not in normal cells), with stem cell marker expression increase. Inhibition of diabetes-increased miRNA-203a targeting WNT5A increased Wnt5a and wound healing in diabetic cells. miRNA-203a inhibitor and WNT5A siRNA reduced wound healing in normal cells. We will identify mechanisms of action of new diabetic marker Wnt5a, its effects on diabetic corneal cell populations, and normalize its levels in diabetic corneal cells. We hypothesize that normalization of diabetes-impaired stem cell phenotype and epithelial wound healing may be achieved by restoring normal expression of noncanonical Wnt5a by blocking its inhibiting microRNA with a novel nanoconjugate and using demethylating agents. Specific Aim 1. To identify Wnt5a receptor(s) mediating its effects on diabetic epithelial cells and corneas. Wnt5a receptors in diabetic limbal cells and corneas will be identified by imaging and functionally, by siRNAs, focusing first on ROR2. This will allow modulating their expression and signaling in diabetic cells to boost Wnt5a effects. Specific Aim 2. To examine Wnt5a effects on epithelial wound healing and limbal cell populations in human organ-cultured diabetic corneas. In these corneas, we will confirm normalizing Wnt5a effects using wound healing and stem cell marker expression. Changes in limbal epithelial differentiated and stem cell populations upon Wnt5a (or inhibitors) treatment will be examined by single cell RNA-seq vs. control normal cells. Specific Aim 3. To test the efficacy of therapies aimed at increasing Wnt5a expression using cultured diabetic cells and organ-cultured corneas. Diabetic limbal epithelial cells and corneas will be treated with nanoconjugate with miR-203a specific antagonist and/or with demethylating 5-Aza-2′-deoxycytidine (Decitabine) or Zebularine. Our aims fit well the priorities set in the NEI Vision Research: Needs, Gaps, and Opportunities. These priorities include (1) improving the transplantation of cultured corneal epithelial cells, (2) understanding of the epigenetic regulation of wound healing, and (3) developing methods to enhance the wound healing process.
糖尿病是劳动年龄成年人中最普遍的致盲疾病。高达70%的糖尿病患者患有糖尿病

项目成果

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Alexander V Ljubimov其他文献

Alexander V Ljubimov的其他文献

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{{ truncateString('Alexander V Ljubimov', 18)}}的其他基金

Targeting tumor microenvironment by nanoimmunodrugs for glioma treatment
纳米免疫药物靶向肿瘤微环境治疗神经胶质瘤
  • 批准号:
    10743942
  • 财政年份:
    2023
  • 资助金额:
    $ 41.75万
  • 项目类别:
Wnt5a, a New Diabetic Corneal Marker Related to Wound Healing
Wnt5a,一种与伤口愈合相关的新糖尿病角膜标记物
  • 批准号:
    10468981
  • 财政年份:
    2020
  • 资助金额:
    $ 41.75万
  • 项目类别:
Wnt5a, a New Diabetic Corneal Marker Related to Wound Healing
Wnt5a,一种与伤口愈合相关的新糖尿病角膜标记物
  • 批准号:
    10254336
  • 财政年份:
    2020
  • 资助金额:
    $ 41.75万
  • 项目类别:
2020 Cornea and Ocular Surface Biology and Pathology GRC/GRS
2020年角膜和眼表面生物学与病理学GRC/GRS
  • 批准号:
    9913789
  • 财政年份:
    2019
  • 资助金额:
    $ 41.75万
  • 项目类别:
Transplantable limbal cells from induced pluripotent stem cells
来自诱导多能干细胞的可移植角膜缘细胞
  • 批准号:
    8659460
  • 财政年份:
    2013
  • 资助金额:
    $ 41.75万
  • 项目类别:
Transplantable limbal cells from induced pluripotent stem cells
来自诱导多能干细胞的可移植角膜缘细胞
  • 批准号:
    8849448
  • 财政年份:
    2013
  • 资助金额:
    $ 41.75万
  • 项目类别:
Transplantable limbal cells from induced pluripotent stem cells
来自诱导多能干细胞的可移植角膜缘细胞
  • 批准号:
    8503490
  • 财政年份:
    2013
  • 资助金额:
    $ 41.75万
  • 项目类别:
Mechanisms of Epithelial Alterations in Diabetic Cornea
糖尿病角膜上皮改变的机制
  • 批准号:
    8042795
  • 财政年份:
    2001
  • 资助金额:
    $ 41.75万
  • 项目类别:
Mechanisms of Epithelial Alterations in Diabetic Cornea
糖尿病角膜上皮改变的机制
  • 批准号:
    8827343
  • 财政年份:
    2001
  • 资助金额:
    $ 41.75万
  • 项目类别:
Mechanisms of Epithelial Alterations in Diabetic Cornea
糖尿病角膜上皮改变的机制
  • 批准号:
    7289238
  • 财政年份:
    2001
  • 资助金额:
    $ 41.75万
  • 项目类别:

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