Functionalized Enzyme Treatments for Dual-Targeting of Inflammation in Spinal Cord Injury

功能化酶治疗脊髓损伤炎症的双重靶向

基本信息

  • 批准号:
    10284992
  • 负责人:
  • 金额:
    $ 41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Unlike other tissues, such as skin and muscle that are capable of complete tissue remodeling, the central nervous system (CNS) lacks the ability to properly heal after injury. Instead, CNS wound repair is marked by sustained glial reactivity and scar tissue deposition, all of which are exacerbated by inflammation. Therapeutic application of the anti-inflammatory methylprednisolone is the only current treatment option for spinal cord injury (SCI), however, it only has acute efficacy and does not resolve tissue remodeling or scarring. This project proposes to investigate idoleamine 2,3-dioxygenase (IDO) as a novel immunomodulatory therapeutic for SCI. IDO is attractive for its dual targeting ability not only to downregulate pro-inflammatory responses but also to promote pro-regenerative cell phenotypes, effectively restoring the imbalance of inflammatory processes after CNS injury. The guiding hypothesis of this research is that IDO will have dual efficacy in immunomodulation of acute systemic inflammation and mitigation of chronic resident cell activation and scarring in the spinal cord. Moreover, the project will investigate two innovative, functionalized forms of IDO for directed targeting of systemic and localized immunomodulation in SCI. First, IDO modified with polyethylene glycol (PEG) will be used for systemic intravenous administration immediately after SCI. PEG improves protein stability in blood and prolongs circulation time, making it an ideal candidate for systemic delivery. PEG-IDO will target circulating leukocytes to modulate early stage inflammation after injury. Secondly, IDO fused with galectin- 3 (Gal3), a glycan binding protein to increase local retention at a tissue target site, will be delivered one week after injury to evaluate effects on resident cell reactivity, reparative immune cell presence, and tissue scarring. The rationale for this design is to better harness IDO’s ability to promote reparative mechanisms in immune cells and glia that are locally present around the lesion site. Co-administration of IDO-Gal3 with key compounds that direct production of neuroprotective metabolites by resident glia (i.e., KMO inhibitors) will further enhance therapeutic effects of localized IDO. Together, this combination will be delivered within a novel, pro-regenerative decellularized neural scaffold to synergistically mitigate neuroinflammation. Overall, the dual immunomodulation potential of IDO provides a new perspective for anti-inflammatory drug administration for CNS injury. The proposed work will demonstrate merit for the individual novel approaches with PEG-IDO and IDO-Gal3 for cell-specific targeting. The long-term goal is to use this mechanistic understanding as a first step in research efforts to develop more effective combination strategies for CNS repair.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Benjamin George Keselowsky其他文献

Benjamin George Keselowsky的其他文献

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{{ truncateString('Benjamin George Keselowsky', 18)}}的其他基金

Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury
指导色氨酸免疫代谢改善肝脏缺血再灌注损伤
  • 批准号:
    10595020
  • 财政年份:
    2022
  • 资助金额:
    $ 41万
  • 项目类别:
Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury
指导色氨酸免疫代谢改善肝脏缺血再灌注损伤
  • 批准号:
    10444213
  • 财政年份:
    2022
  • 资助金额:
    $ 41万
  • 项目类别:
Diversity Supplement: Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury
多样性补充剂:引导色氨酸免疫代谢改善肝脏缺血再灌注损伤
  • 批准号:
    10632561
  • 财政年份:
    2022
  • 资助金额:
    $ 41万
  • 项目类别:
Tissue-Targeted Enzyme for Localized Tryptophan Catabolism to Direct Subcutaneous and Oral Mucosal Inflammatory Responses
用于局部色氨酸分解代谢的组织靶向酶以指导皮下和口腔粘膜炎症反应
  • 批准号:
    9752509
  • 财政年份:
    2017
  • 资助金额:
    $ 41万
  • 项目类别:
Tissue-Targeted Enzyme for Localized Tryptophan Catabolism to Direct Subcutaneous and Oral Mucosal Inflammatory Responses
用于局部色氨酸分解代谢的组织靶向酶以指导皮下和口腔粘膜炎症反应
  • 批准号:
    9403768
  • 财政年份:
    2017
  • 资助金额:
    $ 41万
  • 项目类别:
Biomaterial Delivery System for Type 1 Diabetes Vaccine
1 型糖尿病疫苗的生物材料输送系统
  • 批准号:
    9285796
  • 财政年份:
    2014
  • 资助金额:
    $ 41万
  • 项目类别:
Biomaterial Delivery System for Type 1 Diabetes Vaccine
1 型糖尿病疫苗的生物材料输送系统
  • 批准号:
    8761784
  • 财政年份:
    2014
  • 资助金额:
    $ 41万
  • 项目类别:
Dendritic Cell-Targeting Microparticles for Subcellularly-Targeted Delivery of In
用于亚细胞靶向递送 In 的树突状细胞靶向微粒
  • 批准号:
    8707719
  • 财政年份:
    2012
  • 资助金额:
    $ 41万
  • 项目类别:
Dendritic Cell-Targeting Microparticles for Subcellularly-Targeted Delivery of In
用于亚细胞靶向递送 In 的树突状细胞靶向微粒
  • 批准号:
    9041572
  • 财政年份:
    2012
  • 资助金额:
    $ 41万
  • 项目类别:
Dendritic Cell-Targeting Microparticles for Subcellularly-Targeted Delivery of In
用于亚细胞靶向递送 In 的树突状细胞靶向微粒
  • 批准号:
    8442857
  • 财政年份:
    2012
  • 资助金额:
    $ 41万
  • 项目类别:

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开发作为抗炎剂和砷解毒剂的小分子抑制剂
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