Characterizing antidepressant-like effects of a novel peptide HCN channel inhibitor
表征新型肽 HCN 通道抑制剂的抗抑郁样作用
基本信息
- 批准号:9617909
- 负责人:
- 金额:$ 7.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-23 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Major depressive disorder (MDD) affects millions of people worldwide. Most drugs available to treat MDD
target brain pathways involving monoaminergic neurotransmitters. Because up to fifty percent of patients
do not improve in response to existing therapies, new treatments that target novel mechanisms are
needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate Ih, an important
current for controlling neuronal excitability. Brain HCN channels are tightly regulated by an auxiliary
subunit, TRIP8b (tetratricopeptide repeat-containing Rab8b-interacting protein). Animals lacking TRIP8b
and other HCN subunits exhibit an antidepressant-like phenotype, suggesting that inhibiting HCN channels
could effectively treat depression. Because the channels are critical in controlling heart rate, directly
targeting HCN channels throughout the body is not a viable therapeutic approach. We recently
demonstrated that viral overexpression of TRIP8b in the hippocampus leads to changes in HCN
channel function with concomitant changes in behaviors associated with antidepressant use. In
particular, restoring TRIP8b expression in the hippocampi of TRIP8b knockout mice promoted depression-
like behaviors, while a version of TRIP8b with impaired binding to HCN channel pore-forming subunits
increased antidepressant-like behavior. These results indicate that the TRIP8b-HCN interaction might be a
novel pharmacological target for treating MDD.
Although our recent studies with viral gene therapy strengthen the evidence that inhibiting brain HCN might
be useful for depression treatment, the approach requires surgery and the technology is not readily
translatable to human patients with MDD. On the other hand, inhibitors of the TRIP8b-HCN interaction offer
increased ease of use in probing the role of HCN channels in behavior as well as greater translatability as
potential therapies. Along theses lines, we have synthesized a small (11 amino acids) peptide capable of
binding TRIP8b and blocking the TRIP8b-HCN interaction in vitro. A cell permeable version of this peptide
(SNL-CP) was synthesized to allow the peptide to penetrate the blood-brain barrier and cell membranes. In
preliminary studies, we show that SNL-CP crosses the plasma membrane of CA1 neurons. We
hypothesize that peptide mediated inhibition of TRIP8b's interaction with HCN pore-forming
subunits will promote antidepressant-like behavior. In aim 1, we will assess the ability of SNL-CP to
disrupt the TRIP8b-HCN interaction after chronic intrahippocampal delivery in mice. These experiments will
determine the dosing strategy necessary for therapeutic intervention. In aim 2, we will evaluate the ability of
SNL-CP to promote antidepressant-like behavior in mice. The work described in this proposal will evaluate
a novel approach to producing antidepressant-like behaviors in mice and could pave the way for a new
approach to treating MDD in human patients refractory to existing therapies.
重度抑郁症(MDD)影响着全世界数百万人。大多数药物可用于治疗重度抑郁症
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(0)
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 }}
Dane M Chetkovich其他文献
Dane M Chetkovich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('Dane M Chetkovich', 18)}}的其他基金
Development of in vivo probes to study the function of TRIP8b in cognition
开发体内探针来研究 TRIP8b 在认知中的功能
- 批准号:
10644201 - 财政年份:2022
- 资助金额:
$ 7.77万 - 项目类别:
Development of in vivo probes to study the function of TRIP8b in cognition
开发体内探针来研究 TRIP8b 在认知中的功能
- 批准号:
10665810 - 财政年份:2022
- 资助金额:
$ 7.77万 - 项目类别:
Investigating the Role of the Dorsal Hippocampus to Nucleus Accumbens Pathway in Regulating Social Interaction
研究背侧海马到伏核通路在调节社会互动中的作用
- 批准号:
10381577 - 财政年份:2021
- 资助金额:
$ 7.77万 - 项目类别:
Investigating the Role of the Dorsal Hippocampus to Nucleus Accumbens Pathway in Regulating Social Interaction
研究背侧海马到伏核通路在调节社会互动中的作用
- 批准号:
10195843 - 财政年份:2021
- 资助金额:
$ 7.77万 - 项目类别:
Characterizing antidepressant-like effects of a novel peptide HCN channel inhibitor
表征新型肽 HCN 通道抑制剂的抗抑郁样作用
- 批准号:
9322763 - 财政年份:2017
- 资助金额:
$ 7.77万 - 项目类别:
Discovery of novel small molecule antidepressants
新型小分子抗抑郁药的发现
- 批准号:
9263004 - 财政年份:2016
- 资助金额:
$ 7.77万 - 项目类别:
Discovery of novel small molecule antidepressants
新型小分子抗抑郁药的发现
- 批准号:
9038165 - 财政年份:2016
- 资助金额:
$ 7.77万 - 项目类别:
Evaluation of antidepressant-like effects of hippocampal HCN channel modulation
海马 HCN 通道调节的抗抑郁样作用评价
- 批准号:
8824404 - 财政年份:2014
- 资助金额:
$ 7.77万 - 项目类别:
Evaluation of antidepressant-like effects of hippocampal HCN channel modulation
海马 HCN 通道调节的抗抑郁样作用评价
- 批准号:
8923343 - 财政年份:2014
- 资助金额:
$ 7.77万 - 项目类别:
相似国自然基金
精神创伤相关的抑郁症HPA轴功能与相关脑区磁共振特征研究
- 批准号:81171286
- 批准年份:2011
- 资助金额:58.0 万元
- 项目类别:面上项目
双重作用新抗抑郁药研究——先导物优化、构效关系和作用机理
- 批准号:30572233
- 批准年份:2005
- 资助金额:8.0 万元
- 项目类别:面上项目
抗抑郁剂调控细胞骨架蛋白的功能研究
- 批准号:30472018
- 批准年份:2004
- 资助金额:16.0 万元
- 项目类别:面上项目
相似海外基金
Biochemical Studies Underlying Acute Ethanol's Antidepressant-like effects during Withdrawal in a Preclinical Model of Ethanol Dependence
乙醇依赖临床前模型中戒断期间乙醇急性抗抑郁样作用的生化研究
- 批准号:
10595193 - 财政年份:2023
- 资助金额:
$ 7.77万 - 项目类别:
Mechanisms underlying the antidepressant-like effects of intranasal administration of resolvins in animal models of depression and treatment-resistant depression
在抑郁症和难治性抑郁症动物模型中鼻内施用消退素的抗抑郁样作用的机制
- 批准号:
19K07120 - 财政年份:2019
- 资助金额:
$ 7.77万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Circuit-specific actions of endocannabinoids in stress and mood disorders
内源性大麻素在压力和情绪障碍中的电路特异性作用
- 批准号:
10477473 - 财政年份:2019
- 资助金额:
$ 7.77万 - 项目类别:
The effect of omega-3 polyunsaturated fatty acids on antidepressant-like behavior
omega-3 多不饱和脂肪酸对抗抑郁样行为的影响
- 批准号:
19K08086 - 财政年份:2019
- 资助金额:
$ 7.77万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Circuit-specific actions of endocannabinoids in stress and mood disorders
内源性大麻素在压力和情绪障碍中的电路特异性作用
- 批准号:
10238098 - 财政年份:2019
- 资助金额:
$ 7.77万 - 项目类别:
Circuit-specific actions of endocannabinoids in stress and mood disorders
内源性大麻素在压力和情绪障碍中的电路特异性作用
- 批准号:
10013295 - 财政年份:2019
- 资助金额:
$ 7.77万 - 项目类别:
Circuit-specific actions of endocannabinoids in stress and mood disorders
内源性大麻素在压力和情绪障碍中的电路特异性作用
- 批准号:
10689093 - 财政年份:2019
- 资助金额:
$ 7.77万 - 项目类别:
Analysis of the mechanism underlying the antidepressant-like effects of Kampo medicines focusing on the monoamine nervous system and epigenetics
以单胺神经系统和表观遗传学为重点分析汉方药物抗抑郁样作用的机制
- 批准号:
18K14941 - 财政年份:2018
- 资助金额:
$ 7.77万 - 项目类别:
Grant-in-Aid for Early-Career Scientists