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

描述(申请人提供)：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病理性疼痛。神经病理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的轴突、雪旺细胞和保留的C纤维之间提供通信，这可能在疼痛处理中非常重要。我们推测，调节受损神经内细胞外微环境的受体可能调节神经病理性疼痛。低密度脂蛋白受体相关蛋白-1(LRP-1)是一种多功能受体，可与多种细胞外介质结合，参与PNS损伤的反应。与LRP-1的配体结合导致受体介导的内吞作用和细胞信号转导。我们首次证实了雪旺细胞表达LRP-1，并且神经损伤后雪旺细胞中LRP-1的表达增加。LRP-1表达可能在神经损伤中重要的活动，包括调节雪旺细胞的激活和存活，调节对炎性细胞因子的反应，以及管理髓鞘碎片。LRP-1似乎也调节自发和诱发的疼痛相关行为。本研究的目的是阐明膜锚定LRP-1的功能及其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”的方法来研究LRP-1作为雪旺细胞生物学调节因子在体外、体内坐骨神经损伤和神经病理性疼痛发展中的活性。在目标2中，我们将研究LRP-1配体，它可能是触发依赖于LRP-1的细胞信号通路的关键，该信号通路调节对PNS损伤的反应。最后，在目标3中，我们将阐明LRP-1在清除损伤的坐骨神经中的髓鞘碎片中的作用。总体而言，这些研究将为控制周围神经损伤进展以及神经病理性疼痛的发展和维持的新机制提供洞察力。我们希望阐明雪旺细胞调节神经病理性疼痛的新途径。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。 公共卫生相关性：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，大多数治疗慢性疼痛的疗法都是无效的。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，为我们开发治疗慢性疼痛的新疗法奠定基础。

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.