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：
9322763
负责人：
Dane M Chetkovich
金额：
$ 15.45万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2017-04-01 至 2017-11-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9322763
关键词：
Adverse effects Affect Alpha Cell Amino Acids Animal Model Animals Antidepressive Agents Behavior Binding Biochemistry Blood - brain barrier anatomy Brain Cardiac Cell membrane Cells Cessation of life Chronic Cyclic Nucleotides Data Development Disease Disease remission Dose Electroconvulsive Therapy Electrophysiology (science)Engineering Exhibits Extracellular Space Genes Genetic HCN1 gene Heart Rate High Prevalence Hippocampus (Brain)Human Immunohistochemistry Impairment In Vitro Ion Channel Knock-out Knockout Mice Lead Major Depressive Disorder Mediating Medical Mental Depression Morbidity - disease rate Mus Neuraxis Neurons Neurotransmitters Operative Surgical Procedures Paper Patients Peptides Periodicity Permeability Pharmaceutical Preparations Pharmacology Phenotype Play Proteins Refractory Role Schedule Technology Therapeutic Therapeutic Intervention Viral Viral Genes Viral Vector Work brain pathway cyclic-nucleotide gated ion channels depressed patient depression model disability disorder risk experimental study gene therapy hippocampal pyramidal neuron in vivo inhibitor/antagonist mortality mouse model neuronal excitability new therapeutic target novel novel strategies overexpression response social stigma trafficking

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）影响全球数百万的人。大多数可用于治疗MDD的药物涉及单胺能神经递质的靶向脑途径。因为多达50％的患者不要对现有疗法有所改善，针对新型机制的新疗法是需要。超极化激活的循环核苷酸门控（HCN）通道介导了IH，这是一个重要的控制神经元兴奋性的电流。脑HCN通道由辅助机构严格调节亚基，Trip8b（四肽重复含Rab8b相互作用蛋白）。缺乏Trip8b的动物其他HCN亚基表现出抗抑郁药样表型，表明抑制HCN通道可以有效治疗抑郁症。因为这些通道对于控制心率至关重要，所以直接靶向HCN通道遍布整个身体不是可行的治疗方法。我们最近证明Trip8b在海马中的病毒过表达导致HCN变化与抗抑郁药相关的行为变化的通道功能。在特别是，在TRIP8B敲除小鼠海马中恢复Trip8b表达促进了抑郁症 - 像行为一样，而trip8b的版本与HCN通道孔形成亚基的结合受损增加抗抑郁药样行为。这些结果表明TRIP8B-HCN相互作用可能是治疗MDD的新型药理靶标。尽管我们最近对病毒基因疗法的研究加强了抑制脑HCN的证据对于抑郁症治疗有用，该方法需要手术，并且该技术不容易可翻译成MDD的人类患者。另一方面，TRIP8B-HCN相互作用的抑制剂提供提高了探测HCN通道在行为中的作用以及更大的转换性的易用性潜在疗法。沿这些线条，我们合成了一个小（11个氨基酸）肽结合TRIP8B并在体外阻塞TRIP8B-HCN相互作用。该肽的细胞渗透性版本（SNL-CP）合成以使肽可以穿透血脑屏障和细胞膜。在初步研究，我们表明SNL-CP越过CA1神经元的质膜。我们假设肽介导的Trip8b与HCN孔形成的相互作用的抑制作用亚基将促进抗抑郁药样行为。在AIM 1中，我们将评估SNL-CP的能力小鼠慢性膜体内递送后，破坏TRIP8B-HCN相互作用。这些实验会确定治疗干预所需的给药策略。在AIM 2中，我们将评估 SNL-CP促进小鼠抗抑郁样行为。本提案中描述的工作将评估一种新颖的方法，用于在小鼠中产生类似抗抑郁药的行为，并为新的方式铺平了道路对现有疗法难治性治疗MDD的方法。