MicroRNA-mediated silencing of the Kv4.2 complex in epilepsy

MicroRNA 介导的癫痫 Kv4.2 复合物沉默

基本信息

  • 批准号:
    9414624
  • 负责人:
  • 金额:
    $ 10.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-01-01 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): More than one third of individuals with epilepsy are not seizure-free with currently available treatments. Causes of intractable epilepsy are manifold; yet, elevated and uncontrolled neuronal excitability and synchronicity in the brain are fundamental attributes. Therapies that exploit the brain's intrinsic mechanisms to control excitabil- ity and suppress synchronicity thus hold great promise, but critically depend on a better understanding of these processes. The contribution of the proposed research to this challenge will be to assess microRNA-induced silencing of transient inactivating A-type potassium currents as an inherent mechanism of the brain that con- trols neuronal excitability and could be a therapeutic target for epilepsy. A-type currents are crucial gate keep- ers of excitability and synchronicity in the brain, and defects in A-type current-mediating channel subunits in- crease the susceptibility to seizures and epilepsy. Manipulating these currents could thus be therapeutic in epi- lepsy, but there are currently no specific A-type channel-modulating drugs available. In the brain, A-type cur- rents are mainly mediated by the potassium channel Kv4.2 and its auxiliary subunits (Kv4.2 complex). Protein levels of the Kv4.2 complex are decreased in rodent models of epilepsy, suggesting that downregulation of the Kv4.2 complex is a pathological mechanism in epilepsy. If understood in detail, the mechanisms that lead to this downregulation of the Kv4.2 complex could thus serve as an alternative drug target to manipulate A-type currents. The central hypothesis of this project is that downregulation of Kv4.2 and A-type currents in epilepsy is caused by microRNA-mediated silencing of the Kv4.2 complex, which contributes to neuronal hyperexcitabil- ity and -synchronicity and could thus be a therapeutic target. This hypothesis is supported by strong pilot data showing that inhibition of a Kv4.2-targeting microRNA decreases severity of provoked status epilepticus in mice, reduces kainic acid-induced excitotoxicity in cultured wild type, but not Kv4.2 KO neurons and prevents kainic acid-induced downregulation of Kv4.2 in vitro. Three aims will be pursued. Aim 1 will examine if inhibition of Kv4.2-targeting microRNAs prevents Kv4.2 complex downregulation following seizures and reduces seizure frequency and severity in a mouse model of acquired epilepsy. Aim 2 will identify the most potent Kv4.2- targeting microRNAs by analyzing the mechanisms and quantitatively comparing the efficacy of candidate mi- croRNAs to regulate Kv4.2 complex expression and function. Aim 3 will test the physiological relevance of these findings by expanding the analyses to two mouse models of genetic intractable epilepsy, neuron-specific Pten deletion mice and Cntnap2 KO mice. In contrast to Cntnap2, Pten deletion leads to reduced Kv4.2, ena- bling assessment of increased microRNA-induced Kv4.2 silencing as pathological mechanism and therapeutic target in epilepsy with and without detectable Kv4.2 defects. The approach is innovative, because it will manipulate A-type current expression to modify function. The research is expected to advance knowledge about how the brain regulates excitability, which ultimately could lead to new strategies to treat intractable epilepsy.
 描述(由申请人提供):超过三分之一的癫痫患者在目前可用的治疗下仍无法摆脱癫痫发作。顽固性癫痫的原因是多方面的;然而,大脑中神经元兴奋性和同步性的升高和不受控制是基本属性。因此,利用大脑的内在机制来控制兴奋性和抑制同步性的疗法具有广阔的前景,但关键取决于对这些过程的更好理解。拟议研究对这一挑战的贡献将是评估 microRNA 诱导的短暂失活 A 型钾电流沉默,作为控制神经元兴奋性的大脑固有机制,并可能成为癫痫的治疗靶点。 A 型电流是大脑兴奋性和同步性的关键守门人,A 型电流介导通道亚基的缺陷会增加癫痫发作和癫痫的易感性。因此,操纵这些电流可以治疗癫痫,但目前还没有特定的 A 型通道调节药物。在大脑中,A 型电流主要由钾通道 Kv4.2 及其辅助亚基(Kv4.2 复合体)介导。在癫痫啮齿动物模型中,Kv4.2 复合物的蛋白质水平降低,表明 Kv4.2 复合物的下调是癫痫的病理机制。如果详细了解,导致 Kv4.2 复合物下调的机制可以作为操纵 A 型电流的替代药物靶点。该项目的中心假设是,癫痫中 Kv4.2 和 A 型电流的下调是由 microRNA 介导的 Kv4.2 复合体沉默引起的,这导致神经元过度兴奋和同步性,因此可能成为治疗靶点。这一假设得到了强有力的初步数据的支持,该数据表明,抑制 Kv4.2 靶向 microRNA 可降低小鼠诱发癫痫持续状态的严重程度,降低培养野生型中红藻氨酸诱导的兴奋性毒性,但不会降低 Kv4.2 KO 神经元的兴奋性,并在体外防止红藻氨酸诱导的 Kv4.2 下调。将追求三个目标。目标 1 将检查抑制 Kv4.2 靶向 microRNA 是否可以防止癫痫发作后 Kv4.2 复合物下调,并降低获得性癫痫小鼠模型的癫痫发作频率和严重程度。目标 2 将通过分析机制并定量比较候选 microRNA 调节 Kv4.2 复合体表达和功能的功效,确定最有效的 Kv4.2 靶向 microRNA。目标 3 将通过将分析扩展到两种遗传性难治性癫痫小鼠模型(神经元特异性 Pten 缺失小鼠和 Cntnap2 KO 小鼠)来测试这些发现的生理相关性。与 Cntnap2 相比,Pten 缺失导致 Kv4.2 减少,从而能够评估 microRNA 诱导的 Kv4.2 沉默增加,作为有或没有可检测到的 Kv4.2 缺陷的癫痫的病理机制和治疗靶点。该方法具有创新性,因为它通过操作A型当前表达式来修改函数。这项研究预计将增进人们对大脑如何调节兴奋性的了解,最终可能导致治疗顽固性癫痫的新策略。

项目成果

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Christina Gross其他文献

Christina Gross的其他文献

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{{ truncateString('Christina Gross', 18)}}的其他基金

Cell type-specific functions of microRNA in epilepsy
microRNA 在癫痫中的细胞类型特异性功能
  • 批准号:
    10569048
  • 财政年份:
    2022
  • 资助金额:
    $ 10.24万
  • 项目类别:
Cell type-specific functions of microRNA in epilepsy
microRNA 在癫痫中的细胞类型特异性功能
  • 批准号:
    10427844
  • 财政年份:
    2022
  • 资助金额:
    $ 10.24万
  • 项目类别:
Functional analysis of the microRNA-induced silencing complex in epilepsy
microRNA诱导的沉默复合物在癫痫中的功能分析
  • 批准号:
    10521297
  • 财政年份:
    2019
  • 资助金额:
    $ 10.24万
  • 项目类别:
Functional analysis of the microRNA-induced silencing complex in epilepsy
microRNA诱导的沉默复合物在癫痫中的功能分析
  • 批准号:
    10302281
  • 财政年份:
    2019
  • 资助金额:
    $ 10.24万
  • 项目类别:
Functional analysis of the microRNA-induced silencing complex in epilepsy
microRNA诱导的沉默复合物在癫痫中的功能分析
  • 批准号:
    9886309
  • 财政年份:
    2019
  • 资助金额:
    $ 10.24万
  • 项目类别:
Functional analysis of the microRNA-induced silencing complex in epilepsy
microRNA诱导的沉默复合物在癫痫中的功能分析
  • 批准号:
    10059274
  • 财政年份:
    2019
  • 资助金额:
    $ 10.24万
  • 项目类别:
Functional analysis of the microRNA-induced silencing complex in epilepsy
microRNA诱导的沉默复合物在癫痫中的功能分析
  • 批准号:
    10225865
  • 财政年份:
    2019
  • 资助金额:
    $ 10.24万
  • 项目类别:
MicroRNA-mediated silencing of the Kv4.2 complex in epilepsy
MicroRNA 介导的癫痫 Kv4.2 复合物沉默
  • 批准号:
    9103375
  • 财政年份:
    2016
  • 资助金额:
    $ 10.24万
  • 项目类别:
MicroRNA-mediated silencing of the Kv4.2 complex in epilepsy
MicroRNA 介导的癫痫 Kv4.2 复合物沉默
  • 批准号:
    9241459
  • 财政年份:
    2016
  • 资助金额:
    $ 10.24万
  • 项目类别:
Selective targeting of P13K to restore higher cognitive function in FXS
选择性靶向 P13K 以恢复 FXS 的高级认知功能
  • 批准号:
    8684226
  • 财政年份:
    2014
  • 资助金额:
    $ 10.24万
  • 项目类别:

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