Targeting HDAC6 for the treatment of neuropathic pain

靶向 HDAC6 治疗神经性疼痛

基本信息

批准号：
9387865
负责人：
Venetia Zachariou
金额：
$ 25.43万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2017-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9387865
关键词：
Acetylation Adverse effects Affect Affective Affective Symptoms Alleles Analgesics Anti-Inflammatory Agents Anti-inflammatory Antidepressive Agents Behavior Brain Brain region Brain-Derived Neurotrophic Factor Cells Chemicals Chromatin Chronic stress Data Deacetylase Development Drug usage Dysesthesias Enzymes Gene Expression Genetic Growth Factor HDAC6 gene Heat-Shock Proteins 90 Histone Deacetylase Histone Deacetylase Inhibitor Histones Hyperalgesia Hypersensitivity Intervention Learning LoxP-flanked allele Mechanics Mediating Medical Mental Depression Microtubules Modeling Monitor Moods Motivation Multiprotein Complexes Neurons Nociception Norepinephrine Nuclear Receptors Pain Pain Disorder Patients Perception Peripheral nerve injury Pharmaceutical Preparations Pharmacology Phosphorylation Pre-Clinical Model Prevention Process Property Protein Isoforms Proteins Regulation Role Sensory Serotonin Site Stress Symptoms Testing Therapeutic Time Trichostatin A Tricyclic Antidepressive Agents Tubulin Vorinostat allodynia alpha Tubulin base behavioral response brain cell cell type chronic pain comorbid depression cytokine depression model design improved in vivo inhibitor/antagonist insight loss of function mechanical allodynia mouse model nerve injury new therapeutic target novel novel strategies pain symptom painful neuropathy patient subsets preclinical study raphe nuclei resilience response reuptake spared nerve tool trafficking transmission process

项目摘要

HDAC6, a new therapeutic target for chronic pain Chronic neuropathic pain is a severe medical condition and an important unmet medical need. Current first-line medications successfully provide relief in a subset of patients but their activity usually require weeks to months of administration a delay also observed in preclinical models. In contrast, recent preclinical studies show that broad-acting histone deceatylase (HDAC) inhibitors, such as trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA), rapidly relieve hyperalgesia in various models of neuropathic pain. This points to HDAC inhibition as a promising avenue for the development of new treatments. However, the exact mechanisms underlying this rapid analgesic activity remain elusive. Characterizing the specific HDAC isoforms, the HDAC substrates, and brain networks that mediate these analgesic effects, will provide important insights for the design of newer medications with improved side-effect profile. Our preliminary data indicate that the selective pharmacological blockade of HDAC6, a mainly cytoplasmic class IIB isoform, is sufficient to fully recapitulate the analgesic activity of broad acting HDAC inhibitors, even though this isoform does not deacetylate chromatin in vivo. Under Aim I we will combine state of the art isoform-selective pharmacological probes and conditional loss of function of HDAC6 using a floxed HDAC6 allele to investigate the role of HDAC6 in pain- like behaviors associated with peripheral nerve injury. Specifically, we will use the spare nerve model of neuropathic pain to test the hypothesis that HDAC6 activity at certain supraspinal sites, such as the serotonergic Raphe Nuclei (RN), is necessary and sufficient for the development of sensory hypersensitivity and/or depression-like behaviors. Under Aim II, we will track changes in the expression and activity of HDAC6 at successive time-points after the induction of nerve injury. We will also monitor changes in the phosphorylation of HDAC6 and the acetylation of Hsp90 and alpha-tubulin, two validated targets of HDAC6, under neuropathic pain states. Finally, we will assess the impact of HDAC6 in cytokine expression in the RN.

HDAC6，一个新的慢性疼痛治疗靶点慢性神经性疼痛是严重的医疗状况，并且是重要的未满足的医疗需求。当前的一线药物成功地为一部分患者提供了缓解通常需要在临床前模型中观察到数周到几个月的给药。相比之下，最近的临床前研究表明，广泛的组蛋白结合酶（HDAC）抑制剂，例如trichostatin a（TSA）和suberoylanilide羟氨酸（SAHA），迅速在各种神经性疼痛模型中缓解痛觉过敏。这表明HDAC抑制作用有望开发新治疗的途径。但是，确切的机制这种快速的镇痛活性仍然难以捉摸。表征特定的HDAC 同工型，HDAC底物和介导这些镇痛作用的大脑网络，将提供重要的见解，以设计具有改进的副作用曲线的新药物。我们的初步数据表明，HDAC6的选择性药理阻滞，主要是细胞质IIB类同工型，足以完全概括宽的镇痛活性动作HDAC抑制剂，即使这种同工型不会在体内脱乙酸染色质。在下面目的，我将结合最先进的同工型选择性药理学探针和条件使用Floxed HDAC6等位基因研究HDAC6的功能丧失，以研究HDAC6在疼痛中的作用就像与周围神经损伤相关的行为。具体来说，我们将使用备用神经神经性疼痛的模型，以测试HDAC6在某些脊柱上活性的假设诸如血清素能Raphe核（RN）之类的位点是必要的，足以满足感觉超敏反应和/或类似抑郁症的行为的发展。在AIM II下，我们将在连续的时间点之后，HDAC6表达和活动的轨迹变化诱导神经损伤。我们还将监视HDAC6和HDAC6磷酸化的变化 HSP90和α-微管蛋白的乙酰化，两个经过验证的HDAC6靶标，在神经性疼痛下国家。最后，我们将评估HDAC6在RN中细胞因子表达中的影响。