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（由适用提供）：治疗性低温（TH）方案包括核心体温的轻度降低（32-34¿C），并已证明有效地增加了多次损伤后的生存和功能结果。当前的TH方案涉及通过多种方法进行积极冷却患者，包括冷毯和冰浴，这些方法缓慢，不舒服，并触发颤抖的反应。必须抵消这种颤抖的反应（例如通过肌肉瘫痪），以使身体冷却，并避免发生长时间发抖的临床并发症，例如增加的氧气消耗和高血糖。目前用来防止发抖反应的代理会产生呼吸抑郁症，通常需要患者通风。艰难实施，目标温度的缓慢实现以及与强迫冷却相关的临床并发症的结合限制了传统TH的适用性和潜在有效性。在当前的建议中，我们将通过靶向人体的温暖和冷受体（热受体）来研究药物低温（pH）。据信这些热受体包括瞬时受体电位（TRP）通道家族的温度敏感离子通道。通过单独激活温暖的受体（TRPV1通道）或与抑制冷受体（TRPM8通道）结合使用，我们将降低人体的温度设定点，并采用人体现有的温度调节途径来促进冷却。 AIM 1是一个“原理证明”实验，我们将证明pH在局灶性脑缺血/再灌注的小鼠模型中具有神经保护作用。多个生理变量（例如核心温度，血压和心率）将通过慢性导管或遥测来收集。神经保护措施将通过组织学手段和行为测试恢复28天。 AIM 2将确定TRPV1和TRPM8通道在设定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，还将收集生理变量。体温过低对许多大脑和神经损伤表现出巨大的希望。但是，需要用于产生体温过低的新方法，以提高技术的可用性，2）加快治疗温度的实现，以及3）对身体的压力较小。如果成功的话，我们提出的通过靶向热感受器来降低核心温度的方法可能会显着增加TH的可用性，而在不可能进行传统冷却的环境中，将TH的供应量（在现场，小型医疗诊所，军事战斗环境等）中降低了核心温度。此外，我们预计与传统冷却方案相比，这种方法冷却会产生较小的生理压力。公共卫生相关性：温和的体温过低（将体温降低3至4°C）对许多大脑和神经损伤表现出巨大的希望。但是，需要用于产生体温过低的新方法，以提高该技术的可用性，2）加快治疗温度的实现，3）3）对身体的压力较小。我们提出了通过靶向身体的温度感应神经来降低核心体温的新方法，这可能会显着增加对有意识的患者和患者在无法传统冷却的环境中的可用性。