Targeting thermoreceptors for therapeutic hypothermia

靶向温度感受器进行低温治疗

• 批准号: 8327106
• 负责人: Sean P Marrelli
• 金额: $ 19.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327106
• 关键词: Achievement; Adverse effects; Affect; Animals; Bathing; Blood Pressure; Body Temperature; Brain; Brain Injuries; Catecholamines; Catheterization; Cerebral Ischemia; Cerebrum; Chronic; Clinic; Clinical; Conscious; Effectiveness; Electromyography; Environment; Environmental air flow; Family; Genetic; Goals; Heart Rate; Heating; Histology; Homeostasis; Hour; Hyperglycemia; Ice; Infusion procedures; Intratracheal Intubation; Ion Channel; Ischemic Stroke; Knockout Mice; Measurement; Measures; Medical; Methods; Military Personnel; Multiple Trauma; Mus; Muscle; Narcotics; Nerve; Outcome; Oxygen Consumption; Paralysed; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Protocols documentation; Receptor Activation; Receptor Inhibition; Recovery; Reperfusion Therapy; Role; Sedation procedure; Shivering; Specificity; Speed; Stress; Stroke; Surface; TRPV1 gene; Techniques; Telemetry; Temperature; Temperature Sense; Testing; Therapeutic; Thermoreceptors; Ventilatory Depression; behavior test; combat; functional outcomes; induced hypothermia; inhibitor/antagonist; mouse model; natural hypothermia; nerve injury; neuroprotection; prevent; receptor; research study; response; therapeutic target

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.

描述（由申请人提供）：低温治疗 (TH) 方案包括轻度降低核心体温 (32-34°C)，并已证明可有效提高包括中风在内的多种损伤后的生存率和功能结果。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，这种方法缓慢、不舒服，并会引发颤抖反应。这种颤抖反应必须被抵消（例如通过肌肉麻痹），以使身体冷却，并避免伴随长时间颤抖的临床并发症，例如耗氧量增加和高血糖。目前用于预防颤抖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。 在当前的提案中，我们将通过针对身体的冷热受体（温度感受器）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。通过单独激活暖受体（TRPV1 通道）或结合抑制冷受体（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降温。目标 1 是一个“原理证明”实验，我们将证明 PH 在局灶性脑缺血/再灌注小鼠模型中具有神经保护作用。将通过长期导管插入术或遥测技术收集多种生理变量（例如核心温度、血压和心率）。神经保护作用将通过组织学方法和行为测试来测量，直至恢复 28 天。目标 2 将确定 TRPV1 和 TRPM8 通道在设置低温期间颤抖反应阈值中的作用。除了通过肌电图（EMG）测量颤抖阈值之外，还将如上所述收集生理变量。 低温对于治疗许多脑部和神经损伤有很大的希望。然而，需要新的低温治疗方法，这些方法可以：1）提高技术的可用性，2）加速达到治疗温度，3）减少对身体的压力。如果成功，我们提出的通过靶向温度感受器来降低核心温度的方法可以显着提高无通气意识患者和传统冷却环境中患者（在野外、小型医疗诊所、军事战斗环境等）的 TH 的可用性。此外，我们预计与传统的冷却方案相比，这种冷却方法会产生更少的生理压力。