Synthetic Clamping of Hyperalgesic Signaling

病理性疼痛的部分原因是支持和反对痛觉过敏之间的平衡失调。 伤害性神经元中的信号通路。许多可用的止痛疗法都是为了 抑制特定的痛觉过敏信号或增强特定的抗痛觉过敏信号。然而， 另一种方法是按比例重定向内源性病理促进剂。 痛觉过敏信号转导抗痛觉过敏通路。这样一种方法 可以在不断演变的病理条件下钳制伤害性功能，并且在没有 妥协的保护性疼痛反射。在这项提案中，我们概述了一项将 痛敏原TrkA受体信号转导抑制痛敏原 CAMP和RAS/RAP驱动的信令。我们开发了一个模块化的、可定制的系统， 我们称之为可诱导膜锚定(IMA)，其工作原理是许多 当效应器蛋白被募集到质膜上时，功能最有效，在质膜上，它们的 目标驻留。我们将首先在HEK293细胞中优化该系统，然后转移到培养的小鼠 背根神经节神经元，以确定cAMP和Ras/Rap通路在这些细胞中是否存在 可以通过这种方式进行可控调制。这些研究将作为概念验证 我们的痛觉过敏信号分流系统未来在活体动物模型中的应用可能 导致治疗疼痛的新疗法的发展。此外，我们IMA的模块化 系统使其能够适应广泛的输入信号和输出效应器。工具和 因此，我们形成的概念可能会在神经系统的其他地方和 其他环境，如癌症和免疫学。

Pathological pain results in part from a dysequilibrium between pro- and anti-hyperalgesic signaling pathways in nociceptive neurons. Many available pain therapies are designed to inhibit specific pro-hyperalgesic signals or enhance specific anti-hypergesic signals. However, an alternative approach would be to proportionately redirect endogenous pathological pro- hyperalgesic signaling towards activation of anti-hyperalgesic pathways. Such an approach could clamp nociceptive function under evolving pathological conditions, and do so without compromising protective pain reflexes. In this proposal, we outline a strategy to redirect signaling from the pro-hyperalgesic TrkA receptor to achieve inhibition of pro-hyperalgesic cAMP and Ras/Rap driven signaling. We have developed a modular and customizable system, which we call Inducible Membrane Anchoring (IMA), that operates on the principle that many effector proteins function most efficiently when recruited to the plasma membrane, where their targets reside. We will first optimize this system in HEK293 cells, then move to cultured mouse dorsal root ganglion neurons, to determine if the cAMP and Ras/Rap pathways in those cells can be controllably modulated in this way. These studies will serve as proof-of-concept for future application of our hyperalgesic signal-shunting system in animal models in vivo and may lead to the development of novel therapies for pain. Furthermore, the modularity of our IMA system makes it adaptable to a wide range of input signals and output effectors. The tools and concepts that we develop may therefore have utility elsewhere in the nervous system and in other settings such as cancer and immunology.