Glycine Receptor Expression in Sensory Afferents to Modulate Pain Signaling

感觉传入中甘氨酸受体的表达调节疼痛信号传导

基本信息

项目摘要

DESCRIPTION (provided by applicant): Chronic pain is a major health concern affecting 80 million Americans at some time in their lives. Current pharmacotherapies are not effective long-term, which has led to the development and testing of gene therapy approaches. We and others have demonstrated that herpes simplex virus type 1 (HSV) based vectors can deliver highly effective pain-modulating transgenes to sensory neurons in vivo following inoculation of peripheral tissue. One major advantage of this approach is that painful tissue can be specifically targeted by local vector delivery. We believe that this advantage can be further extended by targeting specific neuron types responsible for chronic pain, thus enabling gene transfer to be tailored to specific types of pain, such as inflammatory or neuropathic pain, while simultaneously reducing deleterious side effects. We have recently shown that HSV-mediated transfer and long-term expression of the glycine receptor 11 subunit (GlyR11) can be used to control the timing and duration of afferent silencing with exogenous administration of glycine. Based on these findings and our recent success in the creation of highly efficient, fully retargeted HSV vectors, we hypothesize that we can selectively silence distinct subpopulations of primary afferents responsible for neuropathic and inflammatory pain, therefore providing injury specific pain relief. These studies will enable us to determine whether the same or different afferent populations underlie inflammatory and neuropathic pain and provide the rational basis for the future development of HSV-based gene transfer vectors designed to restrict analgesia to the relevant primary afferents. We anticipate that these studies will (i) provide a novel platform technology that will allow us to selectively express transgenes designed to modulate the function of sensory afferent subpopulations, a strategy that can be readily extended to other types of sensory nerve disorders; (ii) develop initial functional and physical maps of sensory afferent subtypes that upon silencing will block different persistent pain conditions, thereby providing essential information needed for targeted pain control; (iii) identify afferents that have been functionally altered to respond to painful stimuli providing further information on nerve fiber plasticity; and, (iv) identify potential risks associated with silencing of an inappropriate population of sensory neurons (e.g. altered proprioception). To achieve these goals, we have proposed a series of interrelated experiments described in 3 Specific Aims. In Aim 1, the infectivity of HSV vectors will be retargeted to selectively transduce (a) A2 fibers, (b) peptidergic and (c) nonpeptidergic C fibers. In Aim 2, we will complement transductional retargeting with transcriptional targeting using transgene promoters that will, when combined with transductional targeting, fine tune silencing specificity. The combination strategy is intended to create initial fine maps of subpopulations of sensory fibers within the larger transductionally targeted groups representing critical afferents for the response to different painful stimuli. In Aim 3, the retargeted HSV vectors will be introduced into the DRG by peripheral inoculation of animal models of inflammatory and neuropathic pain and the analgesic efficacy and side effect profiles will be established following glycine-induced GlyR11-mediated silencing.
描述(由申请人提供):慢性疼痛是影响8000万美国人的主要健康问题。当前的药物治疗不是长期有效的,这导致了基因治疗方法的开发和测试。我们和其他人已经证明,基于1型的疱疹病毒(HSV)的载体可以在接种外周组织后向体内的感觉神经元传递高效的疼痛调节转基因。这种方法的一个主要优点是,可以通过局部矢量递送特异性地针对疼痛组织。我们认为,可以通过靶向负责慢性疼痛的特定神经元类型来进一步扩大该优势,从而使基因转移适应特定类型的疼痛,例如炎症或神经性疼痛,同时减少有害的副作用。我们最近表明,HSV介导的甘氨酸受体11亚基(GlyR11)的转移和长期表达可用于控制传入沉默的时间和持续时间,并用外源性甘氨酸施用。基于这些发现以及我们最近在产生高效,完全重新定位的HSV载体方面的成功,我们假设我们可以选择性地沉默负责神经性和炎症性疼痛的主要传入者的不同亚群,从而提供特定于损伤的疼痛。这些研究将使我们能够确定炎症和神经性疼痛的基础相同或不同的传入群体是为了使基于HSV的基因转移媒介的未来发展提供了合理的基础,旨在将镇痛限制在相关的主要传入中。我们预计这些研究将(i)提供一种新型的平台技术,该技术将使我们能够选择性地表达旨在调节感觉传入亚种群功能的转基因,该策略可以很容易地扩展到其他类型的感觉神经疾病; (ii)开发出感官传入亚型的初始功能和物理图,沉默后将阻止不同的持续性疼痛条件,从而提供靶向疼痛控制所需的必要信息; (iii)确定在功能上改变的传入以应对痛苦的刺激,从而提供有关神经纤维可塑性的进一步信息; (iv)确定与不适当的感觉神经元种群沉默有关的潜在风险(例如,本体感受改变)。为了实现这些目标,我们提出了一系列相互关联的实验。在AIM 1中,将将HSV载体的感染性重新定位为选择性转导(a)A2纤维,(b)肽吉尼和(c)非肽G纤维。在AIM 2中,我们将使用转基因启动子与转录靶向相辅相成,这些启动子将与脱节靶向相结合时,微调沉默的特异性。该组合策略旨在在较大的跨描绘群体中创建对感官纤维亚群的初始细微地图,这些靶向群体代表了对不同疼痛刺激的反应的关键传入。在AIM 3中,通过炎性和神经性疼痛的动物模型的周围接种,将引入重定的HSV载体,并在甘氨酸诱导的GllyR11介导的沉积物后建立镇痛功效和镇痛功效。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Joseph C Glorioso其他文献

871 EFFECT OF HERPES SIMPLEX VIRUS (HSV) VECTOR-MEDIATED INTERLEUKIN 4 GENE THERAPY ON ENHANCED BLADDER PAIN BEHAVIOR IN RATS WITH CYCLOPHOSPHAMIDE (CYP)-INDUCED CYSTITIS
  • DOI:
    10.1016/j.juro.2013.02.440
  • 发表时间:
    2013-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tomohiko Oguchi;Hitoshi Yokoyama;Yasuhito Funahashi;Osamu Nishizawa;Satoru Yoshikawa;William F Goins;James R Goss;Joseph C Glorioso;Naoki Yoshimura
  • 通讯作者:
    Naoki Yoshimura
EFFECTS OF HERPES SIMPLEX VIRUS VECTOR-MEDIATED ENKEPHALIN GENE THERAPY ON BLADDER OVERACTICITY AND NOCICEPTION
  • DOI:
    10.1016/s0022-5347(09)60069-0
  • 发表时间:
    2009-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Hitoshi Yokoyama;Chikashi Saitoh;Minoru Miyazato;Osamu Nishizawa;Michael B Chancellor;William F Goins;James R Goss;Joseph C Glorioso;Naoki Yoshimura
  • 通讯作者:
    Naoki Yoshimura
EFFECTS OF DIFFERENT ENKEPHALIN TREATMENTS ON BLADDER PAIN
  • DOI:
    10.1016/s0022-5347(08)60177-9
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Hitoshi Yokoyama;Chikashi Saitoh;Minoru Miyazato;Osamu Nishizawa;Michael B Chancellor;William F Goins;James R Goss;Joseph C Glorioso;Naoki Yoshimura
  • 通讯作者:
    Naoki Yoshimura

Joseph C Glorioso的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Joseph C Glorioso', 18)}}的其他基金

Arming Oncolytic HSV Vectors to Induce Anti-GBM Immune Responses in Syngeneic Mice
武装溶瘤 HSV 载体在同基因小鼠中诱导抗 GBM 免疫反应
  • 批准号:
    9927607
  • 财政年份:
    2018
  • 资助金额:
    $ 36.05万
  • 项目类别:
Arming Oncolytic HSV Vectors to Induce Anti-GBM Immune Responses in Syngeneic Mice
武装溶瘤 HSV 载体在同基因小鼠中诱导抗 GBM 免疫反应
  • 批准号:
    10409654
  • 财政年份:
    2018
  • 资助金额:
    $ 36.05万
  • 项目类别:
Project 1: Arming Oncolytic HSV Vectors to Improve Virolysis in Syngeneic Mouse Models of GBM
项目 1:武装溶瘤 HSV 载体以改善 GBM 同基因小鼠模型中的病毒溶解
  • 批准号:
    10019362
  • 财政年份:
    2013
  • 资助金额:
    $ 36.05万
  • 项目类别:
Project 1: Arming Oncolytic HSV Vectors to Improve Virolysis in Syngeneic Mouse Models of GBM
项目 1:武装溶瘤 HSV 载体以改善 GBM 同基因小鼠模型中的病毒溶解
  • 批准号:
    10491206
  • 财政年份:
    2013
  • 资助金额:
    $ 36.05万
  • 项目类别:
Project 1: Arming Oncolytic HSV Vectors to Improve Virolysis in Syngeneic Mouse Models of GBM
项目 1:武装溶瘤 HSV 载体以改善 GBM 同基因小鼠模型中的病毒溶解
  • 批准号:
    10251082
  • 财政年份:
    2013
  • 资助金额:
    $ 36.05万
  • 项目类别:
Project 1: Treatment of GBM using an oncolytic HSV engineered to improve immunogenic tumor destruction
项目 1:使用经过改造的溶瘤 HSV 治疗 GBM,以改善免疫原性肿瘤破坏
  • 批准号:
    10712280
  • 财政年份:
    2013
  • 资助金额:
    $ 36.05万
  • 项目类别:
Glycine Receptor Expression in Sensory Afferents to Modulate Pain Signaling
感觉传入中甘氨酸受体的表达调节疼痛信号传导
  • 批准号:
    8186007
  • 财政年份:
    2011
  • 资助金额:
    $ 36.05万
  • 项目类别:
Glycine Receptor Expression in Sensory Afferents to Modulate Pain Signaling
感觉传入中甘氨酸受体的表达调节疼痛信号传导
  • 批准号:
    8703184
  • 财政年份:
    2011
  • 资助金额:
    $ 36.05万
  • 项目类别:
Glycine Receptor Expression in Sensory Afferents to Modulate Pain Signaling
感觉传入中甘氨酸受体的表达调节疼痛信号传导
  • 批准号:
    8520405
  • 财政年份:
    2011
  • 资助金额:
    $ 36.05万
  • 项目类别:
Functional Genomic Studies of Early Myogenic Differentiation
早期肌源分化的功能基因组研究
  • 批准号:
    7663827
  • 财政年份:
    2008
  • 资助金额:
    $ 36.05万
  • 项目类别:

相似国自然基金

时空序列驱动的神经形态视觉目标识别算法研究
  • 批准号:
    61906126
  • 批准年份:
    2019
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
  • 批准号:
    41901325
  • 批准年份:
    2019
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
  • 批准号:
    61802133
  • 批准年份:
    2018
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
  • 批准号:
    61872252
  • 批准年份:
    2018
  • 资助金额:
    64.0 万元
  • 项目类别:
    面上项目
针对内存攻击对象的内存安全防御技术研究
  • 批准号:
    61802432
  • 批准年份:
    2018
  • 资助金额:
    25.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Low-dose buccal buprenorphine: Relative abuse potential and postoperative analgesic acceptability
低剂量含服丁丙诺啡:相对滥用潜力和术后镇痛可接受性
  • 批准号:
    10572350
  • 财政年份:
    2023
  • 资助金额:
    $ 36.05万
  • 项目类别:
Identification of Cyclic Peptide Antagonists of an Anti-Opioid G Protein-Coupled Receptor
抗阿片G蛋白偶联受体环肽拮抗剂的鉴定
  • 批准号:
    10256110
  • 财政年份:
    2022
  • 资助金额:
    $ 36.05万
  • 项目类别:
Perioperative Precision Medicine: Translating Science to Clinical Practice to Improve Safety and Efficacy of Opioids in Neonates, Children and Nursing Mothers
围手术期精准医学:将科学转化为临床实践,提高阿片类药物对新生儿、儿童和哺乳期母亲的安全性和有效性
  • 批准号:
    10676237
  • 财政年份:
    2022
  • 资助金额:
    $ 36.05万
  • 项目类别:
Biased Mu-Opioid Receptor Analgesics to Prevent Overdose and Opioid Use Disorders
偏向 Mu-阿片受体镇痛药可预防过量和阿片类药物使用障碍
  • 批准号:
    10539940
  • 财政年份:
    2022
  • 资助金额:
    $ 36.05万
  • 项目类别:
An AI-based Multimodal Approach to Predict Pain in Postnatal Care Scenarios
基于人工智能的多模式方法来预测产后护理场景中的疼痛
  • 批准号:
    10546650
  • 财政年份:
    2022
  • 资助金额:
    $ 36.05万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了