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A Female Specific Role of RGSz1 in Modulation of Chronic Pain

RGSz1 在调节慢性疼痛中的女性特异性作用

基本信息

批准号：
9981335
负责人：
Venetia Zachariou
金额：
$ 43.26万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981335
关键词：
Acute Pain Affect Affinity Attenuated Behavior Biochemical Biochemistry Biological Assay Brain Cell Surface Receptors Data Electrophysiology (science)Elements Enterobacteria phage P1 Cre recombinase Estrogen Nuclear Receptor Estrogen Receptors Female Fractionation G-Protein-Coupled Receptors GTP Phosphohydrolase Activators GTP-Binding Protein Regulators GTP-Binding Protein alpha Subunits, Gs Gene Expression Gene Silencing Genes Genetic Genetic Transcription Golgi Apparatus Gonadal Hormones Hypersensitivity Immunofluorescence Immunologic In Situ Inflammation Label LoxP-flanked allele Maintenance Mediating Messenger RNA Methodology Modeling Molecular Monitor Mus Neurons Nociception Norepinephrine Norepinephrine Receptors Pain Pathologic Pathway interactions Pattern Perception Peripheral Peripheral nerve injury Pharmacology Physiological Play Property Proteins RGS1 gene Regulation Ribosomes Role Sensory Serotonin Signal Transduction Spinal Cord Plasticity Symptoms Testing Thermal Hyperalgesias Transcript Translating Viral Vector Western Blotting Woman Work adeno-associated viral vector base central pain central sensitization chromatin immunoprecipitation chronic pain chronic painful condition inflammatory neuropathic pain knock-down knockout gene male mechanical allodynia men midbrain central gray substance mouse model nerve injury next generation novel overexpression pain model pain processing patch clamp protein expression receptor receptor binding reduce symptoms response serotonin receptor sex transcriptome sequencing transmission process vector

项目摘要

SUMMARY While the mechanisms modulating the transmission and perception of chronic pain differ between men and women, the exact neuroanatomical and molecular differences existing between the sexes remain only partly understood. This proposal focuses on the study of intracellular mechanisms that modulate symptoms of long-term pain states in female mice. We have identified signal transduction mechanisms in the mouse ventrolateral periaqueductal gray (vlPAG) that selectively modulate sensory symptoms of inflammatory and neuropathic pain in female mice. The signal transduction modulator Regulator of G Protein Signaling-1 (RGSz1) controls the function of G protein coupled receptors (GPCRs) by binding to activated Gi subunits, including the Golgi enriched Gz. RGSz1 negatively modulates the amplitude and direction of signal transduction of several GPCRs involved in the modulation of pain processing, including the serotonin 5HT1A receptor. We recently found that RGSz1 mRNA and protein levels are dynamically regulated in the vlPAG of female (but not male) mice by long-term peripheral inflammation. Constitutive deletion of the RGSz1 gene or vlPAG-specific knockdown of RGSz1, exacerbate sensory hypersensitivity behaviors such as thermal hyperalgesia and mechanical allodynia in female mice, but they have no effect in male mice. We will investigate the mechanisms regulating the expression of RGSz1 in the male and female vlPAG at various points after the induction of peripheral nerve injury or inflammation. We will apply several genetic mouse models for regional inactivation or overexpression of RGSz1 in vlPAG neuronal subsets, along with brain biochemistry, electrophysiology and voltammetry to understand the sex-specific role of RGSz1 in the function of the descending inhibitory pathway in models of chronic pain. Since RGSz1 plays a prominent role in the function of the Golgi apparatus, will apply chronic pain models to understand the impact of RGSz1 on the expression levels of trans- Golgi components in the presence and in the absence of pain. Finally, we will use RNA Sequencing to understand the impact of RGSz1 on gene expression adaptations underlying chronic pain states.

总结虽然调节慢性疼痛的传播和感知的机制不同在男性和女性之间，存在着确切的神经解剖学和分子差异，两性之间的关系仍然只是部分了解。本建议的重点是研究调节雌性小鼠长期疼痛状态症状的细胞内机制。我们已经确定了小鼠中脑导水管周围灰质腹外侧的信号转导机制，（vlPAG），其选择性地调节炎性和神经性疼痛的感觉症状。雌性老鼠G蛋白信号转导调节因子1（RGSz 1）通过与活化的G蛋白偶联受体（GPCRs）结合来控制GPCRs的功能亚基，包括富含高尔基体的G β z。RGSz 1负调制幅度，参与疼痛处理调节的几种GPCR的信号转导方向，包括血清素5 HT 1A受体。我们最近发现RGSz 1 mRNA和蛋白质在雌性（而非雄性）小鼠的vlPAG中，外周炎症RGSzl基因的组成性缺失或vlPAG特异性敲低 RGSz 1的表达，加剧感觉超敏反应行为，如热痛觉过敏，机械性异常性疼痛，但它们对雄性小鼠没有影响。我们将调查调节RGSz 1在不同的雄性和雌性vlPAG中表达的机制，穴位后诱发周围神经损伤或炎症。我们将应用几个在vlPAG神经元中RGSz 1的区域失活或过表达的遗传小鼠模型子集，沿着脑生物化学，电生理学和伏安法，以了解 RGSz 1在抑郁模型下行抑制通路功能中的性别特异性作用慢性疼痛由于RGSz 1在高尔基体的功能中起着重要作用，应用慢性疼痛模型来了解RGSz 1对反式- 在存在和不存在疼痛的情况下的高尔基体组件。最后，我们将使用RNA 测序以了解RGSz 1对基因表达适应的影响慢性疼痛状态