Targeting thermoreceptors for therapeutic hypothermia

描述（由申请人提供）：治疗性低温（TH）方案包括轻度降低核心体温（32-34℃），已被证明对增加包括中风在内的多重损伤后的生存率和功能结果有效。目前的TH方案涉及通过各种方法主动冷却患者，包括冷毯和冰浴，这是缓慢的，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），以使身体降温，同时也避免伴随长时间颤抖的临床并发症，如耗氧量增加和高血糖症。目前用于预防寒颤反应的药物会产生呼吸抑制，通常需要患者通气。实施困难、达到目标温度缓慢以及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。在当前的提案中，我们将通过靶向人体的温暖和寒冷受体（热受体）来研究药理学低体温（PH）。这些热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。通过单独激活温暖受体（TRPV1通道）或联合抑制寒冷受体（TRPM8通道），我们将降低身体的温度设定点，并利用身体现有的温度调节途径来促进冷却。目的1是一个“原理证明”实验，我们将证明PH在小鼠局灶性脑缺血/再灌注模型中具有神经保护作用。多种生理变量（如核心温度、血压和心率）将通过慢性导管插入或遥测收集。神经保护将通过组织学方法和行为测试来测量28天的恢复。目的2将确定TRPV1和TRPM8通道在设定低温时寒战反应阈值中的作用。除了通过肌电图（EMG）测量颤抖阈值外，生理变量将如上所述收集。低温疗法对许多脑和神经损伤有很大的疗效。然而，产生低温的新方法是需要的，这些新方法可以：1)增加技术的可用性；2)加快达到治疗温度；3)减少对身体的压力。如果成功，我们提出的通过靶向热感受器降低核心温度的方法可以显着增加非通风意识患者和传统冷却不可能的环境中的患者（在野外，小型医疗诊所，军事战斗环境等）的TH的可用性。此外，我们期望与传统的冷却方案相比，这种冷却方法将产生更少的生理应激。

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.