Mid-sized GDNF Mimics For Neural Regeneration

中型 GDNF 模拟神经再生

基本信息

  • 批准号:
    10811356
  • 负责人:
  • 金额:
    $ 46.47万
  • 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:
    2023-09-19 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary Repair of traumatic injuries relies upon glial cell line-derived neurotrophic factor (GDNF), and related extracellular cytokines collectively called GDNF family ligands (GFLs). GFLs interact with solubilized forms of the GDNF-family receptors (sGFRα1–4) forming complexes which then can bind and activate NCAM (nuclear cell adhesion molecule) and RET (REarranged on Transfection) receptors leading to intracellular signaling and a range of responses conducive to neuronal connectivity. GFLs have been tested in animals and in clinical trials. However, they have poor in vivo stabilities, unfavorable tissue permeation characteristics, and are expensive to prepare with batch-to-batch reproduciblity. Gene therapy approaches have also been attempted, but these are extremely risky because continued expression leads to uncontrollable growth post therapy. Few small molecule mimics of GFL•GFRα interface regions have been reported in the literature. This is surprising because appropriate small molecules could cause conformational changes in sGFRαs transforming them into NCAM/RET agonists which may communicate between cells (trans-signaling) to trigger valuable responses for repair of the peripheral nervous system after trauma. Preliminary studies feature design, synthesis, and testing of two mimics of the GDNF loop which is responsible for most if the GFL•GFRα interface interaction (ie the interface “hot loop”). These loop mimics bind GFRα1 (best so far Kd 240 nM), and are currently being tested in cellular models for repair of traumatic injuries to the peripheral nervous system (PNS). This application is to optimize these initial leads and test them more extensively. Year 1 will focus on on design, syntheses, and GFRα1-binding affinities for similar “cyclo-organopeptide hot loop mimics” by the PI (10 – 20 compounds). Free loop mimics with superior GFRα binding affinities, and samples of ones covalently anchored to hyaluronic acid supports (which mimic the media around synapses), will be selected for Aim 2. The PI is an expert on design and synthesis of growth factor hot loop mimics; he will oversee that part of the work closely. In year 2 the emphasis will shift to testing the best hot-loop mimics identified at that time in 2D and 3D-cellular models for PNS recovery from traumatic injury. Active compounds will also be assayed to test if they cause intracellular activation of NCAM and/or RET. That work will be overseen by Professor Sakiyama, the subcontractor on this application, who has extensive experience with GFLs and supported GFLs, particularly GDNF, tested 2D and 3D cellular assays for neurite outgrowth on sensory and motor neurons. She is an expert in neuronal repair.
项目摘要 创伤性损伤的修复依赖于胶质细胞系源性神经营养因子(GDNF)及其相关蛋白。 细胞外细胞因子统称为GDNF家族配体(GFL)。GFLs与溶解的 GDNF家族受体(sGFRα1-4)形成复合物,然后可以结合, 激活NCAM(核细胞粘附分子)和RET(转染重排)受体 导致细胞内信号传导和一系列有利于神经元连接的反应。 GFLs已经在动物和临床试验中进行了测试。然而,它们具有差的体内稳定性, 不利的组织渗透特性,并且分批制备昂贵 再现性基因治疗方法也曾尝试过,但这些方法风险极高 因为持续的表达导致治疗后不可控的生长。少量小分子 GFL·GFRα界面区的模拟物已在文献中报道。这是令人惊讶 因为适当的小分子可以引起sGFRαs转化的构象变化, 它们转化为NCAM/RET激动剂,其可以在细胞之间进行通信(trans-signaling)以触发 对创伤后周围神经系统的修复有价值的反应。 初步研究功能的设计,合成,并测试两个模拟的GDNF环,这是 如果GFL·GFRα界面相互作用(即界面“热回路”),则对大多数情况负责。这些环 模拟物结合GFRα1(迄今为止最佳Kd 240 nM),目前正在细胞模型中进行测试, 修复周围神经系统(PNS)的创伤性损伤。 此应用程序是为了优化这些初始引线,并更广泛地测试它们.第一年将重点关注 类似“环有机肽热环模拟物”的设计、合成和GFRα1结合亲和力 PI(10 - 20种化合物)。具有上级GFRα结合亲和力的自由环模拟物和样品 共价锚定在透明质酸支持物(模拟突触周围的介质)上, 将被选为目标2。PI是生长因子热环设计和合成的专家 他将密切监督这部分工作。在第二年,重点将转移到测试 当时在2D和3D细胞模型中确定的最佳热循环模拟物,用于PNS从 外伤还将测定活性化合物以测试它们是否引起细胞内活化。 NCAM或RET。这项工作将由该项目的分包商崎山教授监督 应用程序,谁拥有丰富的经验与GFLs和支持的GFLs,特别是GDNF,测试 感觉和运动神经元上神经突生长的2D和3D细胞测定。她是一个专家, 神经修复

项目成果

期刊论文数量(0)
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KEVIN BURGESS其他文献

KEVIN BURGESS的其他文献

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{{ truncateString('KEVIN BURGESS', 18)}}的其他基金

EKO Approach To Find Small Molecules That Perturb Protein Protein Interaction
EKO 方法寻找干扰蛋白质相互作用的小分子
  • 批准号:
    8714576
  • 财政年份:
    2014
  • 资助金额:
    $ 46.47万
  • 项目类别:
IMAGING AND TRACKING OF SINGLE CELL FLUORESCENT PROBES
单细胞荧光探针的成像和跟踪
  • 批准号:
    8362566
  • 财政年份:
    2011
  • 资助金额:
    $ 46.47万
  • 项目类别:
IMAGING AND TRACKING OF SINGLE CELL FLUORESCENT PROBES
单细胞荧光探针的成像和跟踪
  • 批准号:
    8169538
  • 财政年份:
    2010
  • 资助金额:
    $ 46.47万
  • 项目类别:
IMAGING AND TRACKING OF SINGLE CELL FLUORESCENT PROBES
单细胞荧光探针的成像和跟踪
  • 批准号:
    7955433
  • 财政年份:
    2009
  • 资助金额:
    $ 46.47万
  • 项目类别:
Development of an Optimized System for Non-covalent Delivery of Proteins into Cel
开发用于将蛋白质非共价递送至细胞的优化系统
  • 批准号:
    8548535
  • 财政年份:
    2009
  • 资助金额:
    $ 46.47万
  • 项目类别:
Development of an Optimized System for Non-covalent Delivery of Proteins into Cel
开发用于将蛋白质非共价递送至细胞的优化系统
  • 批准号:
    8135036
  • 财政年份:
    2009
  • 资助金额:
    $ 46.47万
  • 项目类别:
Development of an Optimized System for Non-covalent Delivery of Proteins into Cel
开发用于将蛋白质非共价递送至细胞的优化系统
  • 批准号:
    7938881
  • 财政年份:
    2009
  • 资助金额:
    $ 46.47万
  • 项目类别:
IMAGING AND TRACKING OF SINGLE CELL FLUORESCENT PROBES
单细胞荧光探针的成像和跟踪
  • 批准号:
    7723842
  • 财政年份:
    2008
  • 资助金额:
    $ 46.47万
  • 项目类别:
SINGLE CELL FLUORESCENT PROBES
单细胞荧光探针
  • 批准号:
    7598437
  • 财政年份:
    2007
  • 资助金额:
    $ 46.47万
  • 项目类别:
INVESTIGATING NOVEL DNA FLUORSCENCE LABELING PROBES
研究新型 DNA 荧光标记探针
  • 批准号:
    7373136
  • 财政年份:
    2006
  • 资助金额:
    $ 46.47万
  • 项目类别:

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脊髓传入神经元如何控制食欲和口渴
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