Sigma 1 receptor as a master regulator of pronociceptive protein trafficking in t

Sigma 1 受体作为 t 中伤害感受蛋白运输的主要调节因子

基本信息

批准号：
8557220
负责人：
Arnold Eino Ruoho
金额：
$ 28.6万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-05 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8557220
关键词：
Accounting Agonist Anatomic Sites Arts Behavior Behavioral Behavioral Assay Biochemical Bioinformatics Calcium Calcium Signaling Cell membrane Cell physiology Cells Chronic Client Clinical Co-Immunoprecipitations Data Development Effectiveness Endoplasmic Reticulum Environment Etiology Financial cost Formalin G Protein-Coupled Receptor Genes Genetic Horns Human Inflammation Inflammatory Injection of therapeutic agent Injury Knock-out Knockout Mice Mediating Modeling Molecular Motor Neurons Mus Muscarinic M1 Receptor Muscarinics N-Methyl-D-Aspartate Receptors NR1 NMDA receptor NR1 gene Nervous system structure Neuropathy Neuropharmacology Neurosciences Nociception Pain Patients Peptides Pharmaceutical Preparations Phenotype Positioning Attribute Protein Inhibition Proteins Rattus Research Research Personnel Resources Rodent Rodent Model Role Signaling Molecule Signaling Protein Site Site-Directed Mutagenesis Societies Specificity Spinal Spinal Cord Spinal Ganglia Substance P Receptor Techniques Tertiary Protein Structure Testing Therapeutic Universities Up-Regulation Virus Wild Type Mouse Wisconsin Work Yang base chronic constriction injury experience gene therapy in vivo inflammatory neuropathic pain innovation insight nerve injury novel novel therapeutic intervention pain behavior pain inhibition painful neuropathy protein expression protein protein interaction protein transport public health relevance receptor research study sigma-1 receptor skills trafficking

项目摘要

DESCRIPTION (provided by applicant): Neuropathic pain resulting from chronic inflammation and injury to the nervous system is particularly difficult to treat with the currently available drg armamentarium and is a highly problematic unsolved clinical problem. Development of a novel treatment for neuropathic pain is highly significant. Many signaling molecules are likely to partake in the manifestation of neuropathic pain. The Sigma 1 receptor (S1R) is a two-transmembrane mostly endoplasmic reticulum resident protein with many roles in fundamental cellular processes. One of the most robust phenotypes described for the S1R knockout mice is the suppression of neuropathic pain. Intrathecal administration of S1R antagonists mirrors this anti-neuropathic phenotype of the knockout indicating the importance of a spinal segmental level expression of S1R in mediating neuropathic pain. Based on the focused expression of S1R in the ventral horn in the spinal cord proper, we believe S1R in the dorsal root ganglion (DRG) is the key anatomical site of action. We propose a novel concept of the S1R as a master regulator of pronocicptive protein trafficking in the DRG as a mechanism underlying the anti- neuropathic phenotype observed in mice with pharmacological or genetic inhibition of this protein. Preliminary data documents protein:protein interaction between S1R and several pronociceptive proteins including the substance P receptor (NK1R), muscarinic M1 receptor (M1R), and the NR1 subunit of the NMDA receptor all sharing the ability to increase intracellular calcium signaling. Co-expression of S1R increases the plasma membrane expression of NK1R in these cells with a consequent increase in intracellular calcium signaling. We will test the highly innovative working hypothesis that: S1R protein upregulation and modulation of NK1R, M1R, and NMDAR in the dorsal root ganglion (DRG) mediates neuropathic pain. The proposal incorporates state-of-art techniques including a selective in vivo transduction and knockdown of S1R in the DRG by adenoassociated virus 2/8, extensive use of co-immunoprecipitation and novel molecular constructs to decipher the protein domains responsible for the interaction between S1R and the client proteins, and finally examines a gene therapy for neuropathic pain targeting S1R interaction with client proteins.

描述（由申请人提供）：因慢性炎症和神经系统受伤引起的神经性疼痛特别难以治疗当前可用的DRG Armamentarium，并且是一个非常有问题的未解决的临床问题。开发新的神经性疼痛治疗方法非常重要。许多信号分子可能参与神经性疼痛的表现。 Sigma 1受体（S1R）是两种跨膜，主要是内质网势蛋白，在基本细胞过程中具有许多作用。 S1R敲除小鼠描述的最强大的表型之一是抑制神经性疼痛。 S1R拮抗剂的鞘内给药反映了敲除的这种抗神经性表型，表明S1R在介导神经性疼痛中的脊柱分段水平表达的重要性。基于适当的脊髓腹角中S1R的聚焦表达，我们认为背部根神经节（DRG）中的S1R是关键的解剖作用部位。我们提出了一个新的S1R概念，作为DRG中的前介剂蛋白运输的主要调节剂，作为在药理或遗传抑制该蛋白的小鼠中观察到的抗神经性表型的机制。初步数据文献蛋白质：S1R和几种procatianctive蛋白之间的蛋白质相互作用，包括物质P受体（NK1R），毒蕈碱M1受体（M1R）和NMDA受体的NR1亚基，所有蛋白质受体的NR1亚基都具有共享的能力增加细胞内钙信号的能力。 S1R的共表达增加了这些细胞中NK1R的质膜表达，从而导致细胞内钙信号传导增加。我们将测试高度创新的工作假设：在背根神经节（DRG）中NK1R，M1R和NMDAR的S1R蛋白上调和调节可介导神经性疼痛。该提案结合了最先进的技术，包括通过腺体相关病毒2/8的选择性体内转导和S1R敲低的S1R敲低，广泛使用Co-免疫沉淀和新型分子构建体，以破译蛋白质领域的蛋白质与S1R和客户端蛋白质的相互作用，并最终检查perient protiant a Protiant a Protiant a pertion tartiant ose的蛋白质和客户端的相互作用。蛋白质。