LRP-1 is a multifunctional regulator during peripheral nerve injury and pain.

LRP-1 是周围神经损伤和疼痛期间的多功能调节剂。

基本信息

批准号：
7997169
负责人：
WENDY M. CAMPANA
金额：
$ 33.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7997169
关键词：
Applications Grants Astrocytes Axon Behavior Biological Models Brain-Derived Neurotrophic Factor C Fiber Cell Death Cellular biology Collaborations Communication Complex Data Development Extracellular Signal Regulated Kinases Foundations Goals Hand Immunoblot Analysis Immunoblotting In Situ Nick-End Labeling In Vitro Inflammatory Injection of therapeutic agent Injury LDL-Receptor Related Protein 1 Label Letters Ligand Binding Ligands Lipoprotein Receptor Maintenance Mediator of activation protein Membrane Messenger RNA Modeling Molecular Mus Myelin Nerve Nerve Pain Nervous System Trauma Neuroglia Neurons Neuropathy Neuropeptides Outcome Pain Pathway interactions Peptide Hydrolases Peripheral Nervous System Peripheral nerve injury Phagocytosis Procedures Process Proteins Published Comment Rattus Regulation Reporting Research Research Project Grants Resources Role Sampling Schwann Cells Series Signal Pathway Signal Transduction Site Spinal Spinal Ganglia Study Section TNF gene Technology Therapeutic Time Vesicle Work caspase-3 central sensitization chronic neuropathic pain chronic pain cytokine design dorsal horn extracellular flexibility gain of function in vivo injured insight loss of function mitogen-activated protein kinase p38 nerve injury neuronal excitability novel novel strategies novel therapeutics painful neuropathy palliation prevent programs public health relevance receptor receptor binding receptor mediated endocytosis research study response sciatic nerve spontaneous pain success time use

项目摘要

DESCRIPTION (provided by applicant): Direct injury to the sciatic nerve and other major nerves in the peripheral nervous system (PNS) may cause chronic neuropathic pain. Multiple mechanisms are involved in the development and maintenance of neuropathic pain. These mechanisms involve neurons and glia at the site of injury, in the dorsal root ganglia, and in the spinal dorsal horn. At the injury site, diverse extracellular mediators, including cytokines and proteases, provide communication between damaged axons, Schwann cells, and preserved C-fibers, which may be very important in pain processing. We hypothesize that receptors which regulate the extracellular microenviron- ment within the injured nerve may regulate neuropathic pain. The low-density lipoprotein receptor related pro- tein-1 (LRP-1) is a multifunctional receptor that binds numerous extracellular mediators implicated in the res- ponse to PNS injury. Ligand-binding to LRP-1 results in receptor-mediated endocytosis and also in cell-signaling. We have demonstrated for the first time that Schwann cells express LRP-1 and that LRP-1 expression is increased in Schwann cells by nerve injury. LRP-1 expresses activities that may be important in nerve in- jury, including regulation of Schwann cell activation and survival, regulation of the response to inflammatory cytokines, and management of myelin debris. LRP-1 also appears to regulate spontaneous and evoked pain- related behavior. The goal of this research program is to elucidate the function of membrane-anchored LRP-1 and the shed form of the receptor in peripheral nerve injury. In Aim 1, we will apply a series of "loss of function" and "gain of function" approaches to study the activity of LRP-1 as a regulator of Schwann cell biology in vitro, in sciatic nerve injury in vivo, and in the development of neuropathic pain. In Aim 2, we will study LRP-1 ligands, which may be essential in triggering LRP-1-dependent cell-signaling pathways that regulate the res- ponse to PNS injury. Finally, in Aim 3, we will elucidate the role of LRP-1 in the clearance of myelin debris in the injured sciatic nerve. Overall, these studies will offer insight into novel mechanisms that may control the progression of peripheral nerve injury and the development and maintenance of neuropathic pain. We hope to elucidate novel pathways by which Schwann cells regulate neuropathic pain. Furthermore, these studies offer the opportunity for developing novel strategies to treat or prevent neuropathic pain.7. PUBLIC HEALTH RELEVANCE: Direct injury to nerves in the peripheral nervous system may cause chronic pain. Currently, most of the therapeutics for chronic pain treatment are not effective. This grant application seeks to understand the molecular mechanisms underlying peripheral nerve injury and with that understanding, build a foundation in which we can develop novel therapeutics for chronic pain.

描述（由申请人提供）：对坐骨神经和周围神经系统（PNS）中其他主要神经的直接损伤可能会导致慢性神经性疼痛。神经性疼痛的发生和维持涉及多种机制。这些机制涉及损伤部位、背根神经节和脊髓背角的神经元和神经胶质细胞。在损伤部位，包括细胞因子和蛋白酶在内的多种细胞外介质在受损轴突、雪旺细胞和保留的 C 纤维之间提供通讯，这在疼痛处理中可能非常重要。我们假设调节受损神经内细胞外微环境的受体可能调节神经性疼痛。低密度脂蛋白受体相关蛋白-1 (LRP-1) 是一种多功能受体，可结合多种参与三七总皂苷损伤反应的细胞外介质。配体与 LRP-1 的结合导致受体介导的内吞作用以及细胞信号传导。我们首次证明雪旺细胞表达LRP-1，并且神经损伤后雪旺细胞中LRP-1的表达增加。 LRP-1 表达的活性在神经损伤中可能很重要，包括调节雪旺细胞活化和存活、调节对炎性细胞因子的反应以及管理髓鞘碎片。 LRP-1 似乎还调节自发的和诱发的疼痛相关行为。该研究计划的目标是阐明膜锚定 LRP-1 的功能以及该受体在周围神经损伤中的脱落形式。在目标 1 中，我们将应用一系列“功能丧失”和“功能获得”方法来研究 LRP-1 作为雪旺细胞生物学调节剂的体外、体内坐骨神经损伤和神经性疼痛的发展。在目标 2 中，我们将研究 LRP-1 配体，它可能对于触发 LRP-1 依赖性细胞信号传导途径（调节对 PNS 损伤的反应）至关重要。最后，在目标 3 中，我们将阐明 LRP-1 在清除受伤坐骨神经髓鞘碎片中的作用。总体而言，这些研究将深入了解可能控制周围神经损伤进展以及神经性疼痛发生和维持的新机制。我们希望阐明雪旺细胞调节神经性疼痛的新途径。此外，这些研究为开发治疗或预防神经性疼痛的新策略提供了机会。7。公众健康相关性：对周围神经系统神经的直接损伤可能会导致慢性疼痛。目前，大多数慢性疼痛治疗方法均无效。这项拨款申请旨在了解周围神经损伤的分子机制，并以此为基础，为我们开发慢性疼痛的新疗法奠定基础。