Molecular and Genetic Studies of TMEM16C Control of Thermoregulation and Neuronal Excitability

TMEM16C 控制温度调节和神经元兴奋性的分子和遗传学研究

基本信息

  • 批准号:
    9885800
  • 负责人:
  • 金额:
    $ 35.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-15 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

We made the surprise finding that loss of TMEM16C function led to the elimination of the majority of POA neurons that increase their firing rate with rising temperature of the preoptic area of the anterior hypothalamus (POA) – warm-sensitive neurons that are on top of a command chain for thermoregulation. To test for the involvement of TMEM16C in thermoregulation and febrile seizure, we examined TMEM16C conditional knockout (cKO) mice and found that mutant pups with TMEM16C removed from their central neurons cannot maintain their body temperature and are prone to develop hyperthermia-induced seizure. To look for molecular markers of temperature sensitive POA neurons, we conducted single-cell RNAseq of 68 POA neurons following recording from these neurons in brain slices subjected to temperature changes, and validated a molecular and genetic marker for temperature sensitive POA neurons. By generating cKO mice with TMEM16C removed from temperature sensitive POA neurons, we aim to test the function of TMEM16C in the specification of warm-sensitive neurons, thermoregulation, and hyperthermia-induced seizure. Given the GWAS association of TMEM16C with febrile seizure and our finding that rodent pups without neuronal TMEM16C are prone to exhibit hyperthermia-induced seizures, TMEM16C cKO mice provide animal models for febrile seizure, which affects 2-8% of young children. Because complex febrile seizures are associated with hippocampal sclerosis as the epileptogenic pathology, we will test the hypothesis that TMEM16C regulates hippocampal neuronal excitability by recording action potentials and synaptic potentials in hippocampal neurons from mice with TMEM16C removed either via nestin-Cre that is expressed in all neurons or via Drd3-Cre that targets ~50% of hippocampal pyramidal neurons. We will also record from temperature sensitive POA neurons in TMEM16C cKO mice and sibling controls to determine how TMEM16C modulates temperature sensitive POA neuronal activity. We will further test the hypothesis that removing TMEM16C from central neurons causes alteration of sodium-activated potassium current in these neurons. Finally, we will adopt the recently developed split GFP approach involving the use of mass spectrometry to identify proteins that are associated with TMEM16C in specific neuronal types.
我们令人惊讶地发现,TMEM 16 C功能的丧失导致大多数TMEM 16 C基因的消除。 POA神经元,其放电率随着前视区温度的升高而增加 下丘脑(POA)-位于体温调节命令链顶端的温敏神经元。到 为了检测TMEM 16 C参与体温调节和热性惊厥,我们检测了TMEM 16 C 条件性敲除(cKO)小鼠,发现TMEM 16 C从其中枢神经系统中移除的突变幼崽 神经元不能维持它们的体温并且易于发展高血压诱导的癫痫发作。到 为了寻找温度敏感的POA神经元的分子标记物,我们对68个POA神经元进行了单细胞RNAseq, POA神经元,在经历温度变化的脑切片中记录这些神经元, 验证了温度敏感性POA神经元的分子和遗传标记。通过产生cKO小鼠 从温度敏感的POA神经元中去除TMEM 16 C,我们的目的是测试TMEM 16 C的功能 在温敏神经元、体温调节和高血压诱导的癫痫发作的规范中。 考虑到TMEM 16 C与热性惊厥的GWAS关联以及我们的发现, 神经元TMEM 16 C倾向于表现出高血压诱导的癫痫发作,TMEM 16 C cKO小鼠提供了动物 热性惊厥模型,影响2-8%的幼儿。因为复杂性高热惊厥 与海马硬化相关的癫痫病理学,我们将检验这一假设, TMEM 16 C通过记录动作电位和突触电位调节海马神经元兴奋性 在来自TMEM 16 C通过nestin-Cre去除的小鼠的海马神经元中, 神经元或通过Drd 3-Cre靶向约50%的海马锥体神经元。我们还将记录从 TMEM 16 C cKO小鼠和同胞对照中的温度敏感性POA神经元,以确定TMEM 16 C如何 调节温度敏感的POA神经元活动。我们将进一步检验这个假设, 来自中枢神经元的TMEM 16 C引起这些神经元中钠激活钾电流的改变。 最后,我们将采用最近开发的裂解GFP方法,包括使用质谱法, 鉴定在特定神经元类型中与TMEM 16 C相关的蛋白质。

项目成果

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LILY Y JAN其他文献

LILY Y JAN的其他文献

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{{ truncateString('LILY Y JAN', 18)}}的其他基金

The TMEM16 Family of Ion Channels and Lipid Scramblases
TMEM16 离子通道和脂质扰乱系列
  • 批准号:
    10397634
  • 财政年份:
    2021
  • 资助金额:
    $ 35.24万
  • 项目类别:
The TMEM16 Family of Ion Channels and Lipid Scramblases
TMEM16 离子通道和脂质扰乱系列
  • 批准号:
    10221915
  • 财政年份:
    2021
  • 资助金额:
    $ 35.24万
  • 项目类别:
The TMEM16 Family of Ion Channels and Lipid Scramblases
TMEM16 离子通道和脂质扰乱系列
  • 批准号:
    10614438
  • 财政年份:
    2021
  • 资助金额:
    $ 35.24万
  • 项目类别:
Molecular, genetic and physiological studies of calcium-activated chloride channels
钙激活氯离子通道的分子、遗传和生理学研究
  • 批准号:
    10208116
  • 财政年份:
    2020
  • 资助金额:
    $ 35.24万
  • 项目类别:
Central neuronal circuitry for homeostatic thermoregulation modulated by brain temperature
由脑温度调节的稳态体温调节的中枢神经元电路
  • 批准号:
    10709854
  • 财政年份:
    2020
  • 资助金额:
    $ 35.24万
  • 项目类别:
Illuminating Druggable Dark Matter
照亮可药物暗物质
  • 批准号:
    10250493
  • 财政年份:
    2017
  • 资助金额:
    $ 35.24万
  • 项目类别:
Illuminating Druggable Dark Matter
照亮可药物暗物质
  • 批准号:
    9454184
  • 财政年份:
    2017
  • 资助金额:
    $ 35.24万
  • 项目类别:
(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu
(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB):volu
  • 批准号:
    9274826
  • 财政年份:
    2014
  • 资助金额:
    $ 35.24万
  • 项目类别:
(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu
(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB):volu
  • 批准号:
    8686411
  • 财政年份:
    2014
  • 资助金额:
    $ 35.24万
  • 项目类别:
(PQA1) The antipsychotic thioridazine protects against medulloblastoma (MB): volu
(PQA1) 抗精神病药硫利达嗪可预防髓母细胞瘤 (MB):volu
  • 批准号:
    8856184
  • 财政年份:
    2014
  • 资助金额:
    $ 35.24万
  • 项目类别:

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