Targeting thermoreceptors for therapeutic hypothermia

描述(申请人提供)：治疗性低温(TH)方案包括轻微降低核心体温(32-34°C)，已被证明在提高包括中风在内的多重损伤后的存活率和功能结果方面有效。目前的TH方案包括通过各种方法积极为患者降温，包括冷毯和冰浴，这是缓慢、不舒服的，并引发颤抖反应。这种颤抖反应必须被抵消(如肌肉麻痹)，以允许身体降温，并避免伴随着长时间颤抖的临床并发症，如氧气消耗增加和高血糖。目前用于预防寒战反应的药物会产生呼吸抑制，通常需要患者进行通风。实施困难，缓慢达到目标温度，以及与强制冷却相关的临床并发症限制了传统TH的适用性和潜在有效性。在目前的提案中，我们将通过靶向身体的冷暖感受器(热感受器)来研究药理学低温(PH)。这些温度感受器被认为包括瞬时受体电位(Trp)通道家族的温度敏感离子通道。通过单独激活热感受器(TRPV1通道)或与抑制冷感受器(TRPM8通道)相结合，我们将降低人体温度设定点，并利用人体现有的体温调节途径来促进降温。目的1是一个“原则证明”实验，在这个实验中，我们将证明PH对局灶性脑缺血/再灌流小鼠模型具有神经保护作用。多种生理变量(如核心体温、血压和心率)将通过慢性插管或遥测来收集。神经保护将通过组织学方法和行为测试进行测量，直到28天恢复。目的2确定TRPV1和TRPM8通道在设定低温条件下寒战反应阈值中的作用。除了通过肌电(EMG)测量颤抖阈值外，还将收集上述生理变量。低温对一些大脑和神经损伤显示出很大的前景。然而，需要新的产生低温的方法，这些方法可以1)增加技术的可用性，2)加速达到治疗温度，3)对身体产生较少的压力。如果成功，我们提出的通过靶向温度感受器来降低核心温度的方法可以显著增加非呼吸机清醒患者和传统降温不可能的环境中(野外、小型医疗诊所、军事战斗环境等)患者的TH可用性。此外，我们预计，与传统的降温方案相比，这种降温方法将产生较小的生理应力。

DESCRIPTION (provided by applicant): Therapeutic hypothermia (TH) protocols consist of mild lowering of core body temperature (32-34¿C) and have proven effective in increasing survival and functional outcome following multiple injuries including stroke. Current TH protocols involve actively cooling patients by a variety of methods including cold blankets and ice baths which is slow, uncomfortable, and triggers a shiver response. This shiver response must be counteracted (such as by muscle paralysis) to allow body cooling and also to avoid clinical complications that accompany prolonged shivering such as increased oxygen consumption and hyperglycemia. The agents currently used to prevent the shiver response produce respiratory depression and typically require patient ventilation. The combination of difficult implementation, slow achievement of target temperature, and clinical complications associated with forced cooling limits the applicability and potential effectiveness of traditional TH. In the current proposal, we will investigate pharmacological hypothermia (PH) through targeting the body's warm and cold receptors (thermoreceptors). These thermoreceptors are believed to include temperature sensitive ion channels of the transient receptor potential (TRP) channel family. By activating warm receptors (TRPV1 channels) alone or in combination with inhibiting cold receptors (TRPM8 channels), we will lower the body's temperature set point and employ the body's existing thermoregulatory pathways to promote cooling. Aim 1 is a "proof of principle" experiment in which we will demonstrate that PH is neuroprotective in a mouse model of focal cerebral ischemia/reperfusion. Multiple physiologic variables (such as core temperature, blood pressure, and heart rate) will be collected by chronic catheterization or telemetry. Neuroprotection will be measured by histological means and behavioral testing out to 28 days recovery. Aim 2 will determine the role of TRPV1 and TRPM8 channels in setting the threshold of the shiver response during hypothermia. Physiologic variables will be collected as above in addition to measurements of shiver threshold by electromyography (EMG). Hypothermia shows great promise for a number of brain and nerve injuries. However, new methods for producing hypothermia are needed that can 1) increase the availability of the technique, 2) speed the achievement of therapeutic temperature, and 3) produce less stress on the body. If successful, our proposed method of lowering core temperature by targeting thermoreceptors could significantly increase the availability of TH to non-ventilated conscious patients and patients in environments where traditional cooling is not possible (in the field, small medical clinics, military combat setting, etc.). In addition, we expect that this method of cooling will produce less physiologic stress compared with traditional cooling protocols.