Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing

用于角膜伤口愈合的 c-Cbl 拮抗剂的化学优化

基本信息

  • 批准号:
    10557187
  • 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:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary An intact and fully differentiated corneal epithelium is critical for proper vision and to keep foreign objects (bacteria, viruses, small particles) out of the eye. However, damage to the corneal epithelium is one of the most common ocular problems presented in primary care facilities and arises from a variety of factors, including trauma, disease, and a side-effect of drugs. Despite the prevalence, discomfort, and potential for blindness associated with perturbation of the corneal epithelium, there are no FDA-approved agents that promote the restoration and homeostasis of this tissue. The long-term goal of our research is to develop new compounds that promote corneal epithelial wound healing and homeostasis. The overall objective of this application is to chemically optimize a recently identified c-Cbl antagonist to increase its affinity and potency, while decreasing cytotoxicity. To accomplish this, we will test the central hypothesis that compounds that disrupt EGFR:c-Cbl interactions will prevent EGFR ubiquitylation, divert the activated EGFR from the lysosome, and prolong EGFR signaling. Based on preliminary studies, this prolongs EGFR activity and increases the restoration and maintenance of corneal epithelium via cell migration, proliferation, and differentiation. The rationale for these studies is that knockdown of c-Cbl and inhibits EGFR ubiquitylation, prolongs EGFR activity, and enhances corneal epithelial wound healing. Following an in silico screen of 25,000,000 compounds, we have identified several lead compounds that bind c-Cbl and inhibit ligand-mediated EGFR ubiquitylation. We seek to develop the top compound into a therapeutic agent with the following specific aims. In Aim 1, we will structurally optimize our lead compound to increase its affinity for c-Cbl and disrupt EGFR:c-Cbl binding. Multiple rounds of chemical modifications to our lead compound will be used to identify new derivatives that bind recombinant c-Cbl with high affinity and disrupt EGFR:c-Cbl interactions. In Aim 2, we will test the highest affinity compounds for disruption of c-Cbl-mediated ubiquitylation and trafficking of the EGFR. The top candidates will be tested for their ability to block ligand-mediated EGFR ubiquitylation and lysosomal degradation, and if they prolong EGFR signaling in corneal epithelial cells. In Aim 3, we will determine whether inhibitors of EGFR ubiquitylation promote corneal epithelial wound healing. The top compounds will be assayed for corneal epithelial wound healing using in vitro, ex vivo, and in vivo assays. Our proposed studies are innovative, in our opinion, because we will by-pass the limitation of EGFR occupancy and target a novel protein (c-Cbl) and molecular mechanism (receptor desensitization). These studies are significant because accelerating re-epithelialization and homeostasis of compromised corneas will decrease patient distress, minimize infections, and reduce the incidence of blindness. Corneal epithelial homeostasis is a major public health issue with limited treatments. Our goal is to develop our lead compounds for the topical treatment of compromised corneal epithelium to restore tissue homeostasis.
项目总结

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Collagen Mimetic Peptides Promote Corneal Epithelial Cell Regeneration.
  • DOI:
    10.3389/fphar.2021.705623
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Baratta RO;Del Buono BJ;Schlumpf E;Ceresa BP;Calkins DJ
  • 通讯作者:
    Calkins DJ
Modulating Growth Factor Receptor Signaling to Promote Corneal Epithelial Homeostasis.
  • DOI:
    10.3390/cells12232730
  • 发表时间:
    2023-11-29
  • 期刊:
  • 影响因子:
    6
  • 作者:
  • 通讯作者:
Prime time for the recycling endosome.
回收内体的黄金时间。
  • DOI:
    10.15252/embj.2021108758
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ceresa,BrianP
  • 通讯作者:
    Ceresa,BrianP
Epidermal Growth Factor Receptor Expression in the Corneal Epithelium.
  • DOI:
    10.3390/cells10092409
  • 发表时间:
    2021-09-13
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Peterson JL;Ceresa BP
  • 通讯作者:
    Ceresa BP
Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation.
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BRIAN P. CERESA其他文献

BRIAN P. CERESA的其他文献

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{{ truncateString('BRIAN P. CERESA', 18)}}的其他基金

Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing
用于角膜伤口愈合的 c-Cbl 拮抗剂的化学优化
  • 批准号:
    10328929
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Summer Vision Sciences Training Program
夏季视觉科学培训计划
  • 批准号:
    10410169
  • 财政年份:
    2017
  • 资助金额:
    $ 38.5万
  • 项目类别:
Summer Vision Sciences Training Program
夏季视觉科学培训计划
  • 批准号:
    10630145
  • 财政年份:
    2017
  • 资助金额:
    $ 38.5万
  • 项目类别:
Identifying novel c-Cbl antagonists to promote corneal epithelial regeneration
鉴定新型 c-Cbl 拮抗剂以促进角膜上皮再生
  • 批准号:
    9319273
  • 财政年份:
    2016
  • 资助金额:
    $ 38.5万
  • 项目类别:
Identifying novel c-Cbl antagonists to promote corneal epithelial regeneration
鉴定新型 c-Cbl 拮抗剂以促进角膜上皮再生
  • 批准号:
    9165379
  • 财政年份:
    2016
  • 资助金额:
    $ 38.5万
  • 项目类别:
Modulation of EGFR Signaling to Promote Corneal Epithelial Wound Healing
调节 EGFR 信号传导促进角膜上皮伤口愈合
  • 批准号:
    8600276
  • 财政年份:
    2012
  • 资助金额:
    $ 38.5万
  • 项目类别:
Modulation of EGFR Signaling to Promote Corneal Epithelial Wound Healing
调节 EGFR 信号传导促进角膜上皮伤口愈合
  • 批准号:
    8394916
  • 财政年份:
    2012
  • 资助金额:
    $ 38.5万
  • 项目类别:
Modulation of EGFR Signaling to Promote Corneal Epithelial Wound Healing
调节 EGFR 信号传导促进角膜上皮伤口愈合
  • 批准号:
    8236586
  • 财政年份:
    2012
  • 资助金额:
    $ 38.5万
  • 项目类别:
EGFR-MEDIATED CORNEAL EPITHELIAL WOUND HEALING
EGFR 介导的角膜上皮伤口愈合
  • 批准号:
    8360408
  • 财政年份:
    2011
  • 资助金额:
    $ 38.5万
  • 项目类别:
Regulation of EGFR Signaling by the Endocytic Pathway
内吞途径对 EGFR 信号转导的调节
  • 批准号:
    7991730
  • 财政年份:
    2010
  • 资助金额:
    $ 38.5万
  • 项目类别:

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