Synthetic Clamping of Hyperalgesic Signaling

病理性疼痛部分是由亲痛觉过敏和抗痛觉过敏之间的不平衡引起的。 伤害感受神经元的信号通路。许多可用的疼痛疗法旨在 抑制特异性促痛觉过敏信号或增强特异性抗痛觉过敏信号。然而，在这方面， 另一种方法是将内源性病理性前体 痛觉过敏信号传导朝向抗痛觉过敏通路的激活。这种做法 可以在不断发展的病理条件下抑制伤害感受功能， 损害保护性疼痛反射。在这份提案中，我们概述了一项战略， 来自促痛觉过敏TrkA受体的信号传导以实现促痛觉过敏TrkA受体的抑制。 cAMP和Ras/Rap驱动的信号传导。我们开发了一个模块化和可定制的系统， 我们称之为可诱导膜转运（IMA），它的工作原理是， 效应蛋白在被募集到质膜时发挥最有效的功能，在质膜上， 目标存在。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，以确定这些细胞中的cAMP和Ras/Rap通路 可以以这种方式可控地调制。这些研究将作为概念验证， 我们的痛觉过敏信号分流系统在体内动物模型中的未来应用， 导致了新的疼痛疗法的发展。此外，我们IMA的模块化 系统使其适用于广泛的输入信号和输出效应器。的工具和 因此，我们发展的概念可能在神经系统的其他地方以及在 其他设置，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.