Mechanisms controlling distinct modes of adult axon growth

控制成人轴突生长不同模式的机制

基本信息

  • 批准号:
    9129772
  • 负责人:
  • 金额:
    $ 32.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2020-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Affecting axonal growth as a means to enhance recovery and alleviate pathology in conditions of nervous system injury, insult, or disease is a major goal for the healthcare and biomedical research endeavors. Significant effort is directed at inducing neural plasticity to enhance axonal growth to establish functionally- adaptive connections. However, these efforts must also prevent, and not induce, maladaptive plasticity, a balance which requires a clear understanding of the processes regulating axon growth. A major factor confounding efforts to understand neural plasticity is that the traumatically-injured nervou system contains both directly-injured axons and the NON-injured axons. This project examines the long-standing question and controversy regarding the mechanisms of the two major forms of axon growth in the adult nervous system - growth of injured axons (Regeneration) and that of non-injured axons (Collateral Sprouting - CS). We aim to objectively determine the degree to which the intrinsic molecular mechanisms controlling these processes are similar or different. Doing so will enable identification of sets of genes which control a specific mode and may thus be targeted to affect just that one mode, or may be shared between modes and thus targeted to affect both, and could identify an entire new set of genes capable of regulating adult axonal plasticity. Axonal Regeneration and CS are both relatively robust in the PNS, and the injured and non-injured neurons can be clearly separated. Nerve crush provides a model of successful axon regeneration. Using the spared dermatome model (where intact non-injured neurons of a single dorsal root ganglion are induced to grow by denervating the skin bordering their dermatome) we have generated a transcriptomic profile of genes regulated during CS. Bioinformatic analyses indicate that the genes involved in regeneration and CS are highly distinct. Preliminary data using mice with genetic deletion of transcription factors (TFs) that appear to be specific for each axon growth mode supports the concept that the growth modes involve separate genetic programs. Aim 1 will use mice with mode-specific-TF knockout to thoroughly examine the impact of the gene- deletions on the different modes of axon growth using behavioral and histological assessments of axon growth. This will determine if the flagship mode-specific-TFs are indeed responsible for controlling that single mode. We have data demonstrating 1) a mutually-exclusive expression of the mode-specific TFs and 2) that "conditioning" with one mode of growth appears to influence the functional execution of the other mode. This is rational considering that there must be a large change in which genes are expressed, and proper orchestration of such a significant change could be delayed or prevented. Aim 2 will test the hypothesis that the modes negatively-influence each other and involve mutually-exclusive genetic programs by alternately applying the different models to the same neurons (i.e., regeneration-then-sprouting or sprouting-then-regeneration). This will determine how execution of one mode influences the other. For both Aims, experimental outcomes in accord with preliminary data would strongly support the concept that there are indeed two different growth modes, each with distinct genetic control. Outcomes contrary to preliminary data could include 1) effects on some neural populations but not others, which would suggest that there may still be distinct modes with distinct genetic control, but that these modes may be based not on injury- status, but on cell-type, and/or 2) that the apparent mode-specific genetic control systems act as facilitators but are not necessary (i.e., in their absence the processes occur anyway, but much more slowly), which would suggest that there are not necessarily two fully-distinct modes. All outcomes will serve to address both the conceptual framework and the specific molecular control regarding axon growth in the adult nervous system.
 描述(由申请人提供):影响轴突生长作为在神经系统损伤、损伤或疾病的情况下促进恢复和减轻病理的手段是医疗保健和生物医学研究努力的主要目标是诱导神经可塑性。然而,这些努力还必须防止而不是诱发适应不良的可塑性,这种平衡需要清楚地了解调节轴突生长的过程。理解神经可塑性的令人困惑的努力是,创伤性损伤的神经系统同时包含直接损伤的轴突和未损伤的轴突。该项目研究了关于轴突生长的两种主要形式的机制的长期存在的问题和争议。成人神经系统 - 受伤轴突的生长(再生)和未受伤轴突的生长(侧枝发芽 - CS) 我们的目标是客观地确定内在轴突的生长程度。控制这些过程的分子机制是相似或不同的,这将能够识别控制特定模式的基因组,因此可以有针对性地影响一种模式,或者可以在模式之间共享,从而有针对性地影响两种模式。可以识别出能够调节成人轴突可塑性的全新基因组,并且 CS 在 PNS 中都相对强大,并且可以清楚地区分受损和未受伤的神经元,从而提供了成功的轴突再生的模型。使用幸存的皮节模型(通过去神经化其皮节边界的皮肤来诱导单个背根神经节的完整未受伤神经元生长),我们生成了 CS 期间调节的基因的转录组图谱,表明参与再生和 CS 的基因。使用具有转录因子(TF)遗传删除的小鼠的初步数据似乎是针对每种轴突生长模式的,这支持了生长模式涉及单独的遗传程序的概念。 1 将使用模式特异性 TF 敲除的小鼠,通过轴突生长的行为和组织学评估来彻底检查基因缺失对不同轴突生长模式的影响,这将确定旗舰模式特异性 TF 是否确实是。我们有数据证明:1)特定模式转录因子的互斥表达;2)一种生长模式的“调节”似乎会影响另一种模式的功能执行。考虑到有目标 2 必须是基因表达的巨大变化,并且可以延迟或阻止这种重大变化的适当协调,通过交替应用这些模式来检验这些模式相互负面影响并涉及相互排斥的遗传程序的假设。对于相同的神经元使用不同的模型(即强烈再生然后萌芽或萌芽然后再生),这将决定一种模式的执行如何影响另一种模式,根据初步数据的实验结果将支持这一概念。那确实有两种不同的生长模式,每种模式都有与初步数据相反的不同的遗传控制,结果可能包括:1)对某些神经群体的影响,但对其他神经群体没有影响,这表明可能仍然存在具有不同遗传控制的不同模式。模式可能不是基于损伤状态,而是基于细胞类型,和/或2)明显的模式特异性遗传控制系统充当促进者,但不是必需的(即,在它们不存在的情况下,过程无论如何都会发生,但很多更慢),这表明不一定存在两种完全不同的模式。所有结果都将有助于解决有关成人神经系统轴突生长的概念框架和特定分子控制。

项目成果

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Jeffrey C Petruska其他文献

Jeffrey C Petruska的其他文献

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{{ truncateString('Jeffrey C Petruska', 18)}}的其他基金

Developing Novel Models for Assessing Fundamental Mechanisms of Neuroma
开发评估神经瘤基本机制的新模型
  • 批准号:
    10261081
  • 财政年份:
    2021
  • 资助金额:
    $ 32.18万
  • 项目类别:
Developing Novel Models for Assessing Fundamental Mechanisms of Neuroma
开发评估神经瘤基本机制的新模型
  • 批准号:
    10507778
  • 财政年份:
    2021
  • 资助金额:
    $ 32.18万
  • 项目类别:
Defining CAMK4 transcript isoforms for axonal plasticity
定义轴突可塑性的 CAMK4 转录亚型
  • 批准号:
    10317841
  • 财政年份:
    2021
  • 资助金额:
    $ 32.18万
  • 项目类别:
Mechanisms controlling distinct modes of adult axon growth
控制成人轴突生长不同模式的机制
  • 批准号:
    9010096
  • 财政年份:
    2015
  • 资助金额:
    $ 32.18万
  • 项目类别:
Mechanisms controlling distinct modes of adult axon growth
控制成人轴突生长不同模式的机制
  • 批准号:
    9333978
  • 财政年份:
    2015
  • 资助金额:
    $ 32.18万
  • 项目类别:
Mechanisms controlling distinct modes of adult axon growth
控制成人轴突生长不同模式的机制
  • 批准号:
    9750847
  • 财政年份:
    2015
  • 资助金额:
    $ 32.18万
  • 项目类别:
Electrophysiological reporter for monitoring gene manipulations
用于监测基因操作的电生理报告器
  • 批准号:
    8244231
  • 财政年份:
    2011
  • 资助金额:
    $ 32.18万
  • 项目类别:
Electrophysiological reporter for monitoring gene manipulations
用于监测基因操作的电生理报告器
  • 批准号:
    8320092
  • 财政年份:
    2011
  • 资助金额:
    $ 32.18万
  • 项目类别:

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