Programmable molecular nanorobots for treatment of chronic pain and epilepsy

神经系统中信息的正确检测和处理高度依赖于神经元网络控制和调节单个神经元的兴奋性水平（内在兴奋性）和将它们连接成功能网络的突触（网络兴奋性）的能力。兴奋性的调节对于回路适应环境变化的能力至关重要，而内在和网络兴奋性的不受控制的改变会导致正常神经元功能的严重中断。这种不受控制的变化的典型表现是慢性疼痛和癫痫。这些破坏性的医疗条件达到大流行的规模，导致极端的痛苦，以及高昂的医疗费用。尽管做出了广泛的努力，但慢性疼痛和癫痫的有效治疗仍然难以捉摸。这是绝对必要的，以设计治疗策略，选择性地针对异常过程造成慢性疼痛或癫痫发作。在这里，我们建议使用新的，突破性的技术来检测和控制这些类型的异常神经元活动。为此，我们将设计可编程的DNA纳米机器人，它可以感知神经元活动的特定模式，并通过释放选定的调节剂做出反应，从而只影响病理事件，而不影响正常功能。使用DNA纳米机器人，我们将尝试在多个层面上干扰疼痛和癫痫发作。这个多学科的项目将结合尖端的纳米技术与电生理学，多光子成像和行为方法学，这些方法学已经过微调，以研究和控制疼痛和癫痫相关的机制。该提案的结果有望为治疗慢性疼痛和癫痫的新平台提供基础，并对过度兴奋状态的机制产生基本见解。

Proper detection and processing of information in the nervous system is highly dependent on the ability of neuronal network to control and regulate the excitability levels of individual neurons (intrinsic excitability) and the synapses that connect them into a functional network (network excitability). Regulation of the excitability is crucial for the ability of the circuits to adapt to changes in the environment, whereas uncontrolled alteration of intrinsic and network excitability leads to severe interruption of normal neuronal function. The archetypical manifestations of such uncontrolled changes are expressed as chronic pain and epilepsy. These devastating medical conditions reaching pandemic scale, lead to extreme suffering, as well as to exorbitant medical expenses. Despite extensive efforts, effective treatment for chronic pain and epilepsy remains elusive. It is absolutely necessary to design treatment strategies which selectively targets aberrant processes causing chronic pain or epileptic seizures. Here, we propose to use novel, ground-breaking technologies to detect and control these types of abnormal neuronal activity. To that end, we will design programmable DNA nanorobots that can sense specific modes of neuronal activity and respond by releasing selected modulators, thus affecting only pathological events, while sparing normal functions. Using DNA nanorobots, we will attempt to interfere with pain and seizure generation at multiple levels. This multi-disciplinary project will incorporate cutting edge nano-technologies together with electrophysiological, multiphoton imaging and behavioural methodologies, which have been fine-tuned to study and control pain- and epilepsy-reIated mechanisms. The results of this proposal are expected to provide a basis for novel platforms for treating chronic pain and epilepsy, as well as to yield fundamental insights into themechanisms of hyperexcitable states.