Targeting thermoreceptors for therapeutic hypothermia

靶向温度感受器进行低温治疗

基本信息

批准号：
8233629
负责人：
Sean P Marrelli
金额：
$ 23.48万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233629
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Mild hypothermia (lowering of body temperature by 3 to 4¿C) 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 this technique, 2) speed the achievement of therapeutic temperature, and 3) produce less stress on the body. We propose new methods for lowering core body temperature by targeting the temperature- sensing nerves of the body which could significantly increase the availability of mild hypothermia to conscious patients and patients in environments where traditional cooling is not possible.

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。当前的 TH 方案涉及主动降温。通过各种方法给患者降温，包括冷毯和冰浴，这种方法缓慢、不舒服，并且会引发颤抖反应，必须抵消这种颤抖反应（例如通过肌肉麻痹）以使身体冷却。还避免了伴随长时间颤抖而产生的临床并发症，例如耗氧量增加和高血糖，目前用于预防颤抖反应的药物通常需要患者通气，但实施起来困难，达到目标温度缓慢，而且临床效果不佳。与强制冷却相关的并发症限制了传统 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热感受器和冷感受器（温度感受器）来研究药理学低温 (PH)。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的温度设定点。目标 1 是一项“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。（例如核心温度、血压和心率）将通过长期导管插入术或遥测技术收集，并通过组织学方法和行为测试进行测量，直至 28 天恢复，目标 2 将确定 TRPV1 和 TRPM8 通道在恢复中的作用。除了通过肌电图 (EMG) 测量颤抖阈值之外，还可以按上述方式设置体温过低时颤抖反应的阈值，这对许多人来说显示出巨大的前景。然而，需要新的低温治疗方法：1）提高技术的可用性，2）加速达到治疗温度，3）如果成功的话，可以减少对身体的压力。通过针对温度感受器来降低核心温度的方法可以显着提高非通气意识患者和传统冷却环境中的患者（在野外、小型医疗诊所、军事战斗环境等）的 TH 的可用性。，我们期望与传统的冷却方案相比，这种冷却方法产生的生理压力更小。公共健康相关性：轻度低温（体温降低 3 至 4°C）对于许多脑部和神经损伤显示出巨大的希望，但是，需要新的低温方法来：1）提高该技术的可用性， 2）加速达到治疗温度，3）减少对身体的压力我们提出了通过针对身体温度感应神经来降低核心体温的新方法，这可以显着提高可用性。为意识清醒的患者和处于传统冷却无法实现的环境中的患者提供轻度低温治疗。