Role of TRPM8 in Cold-stored Platelet Transfusions

项目总结 通过人体组织中的神经感受器检测温度变化是一种维持生命的方法 高度进化选择的功能。血小板对寒冷表现出独特的反应 细胞骨架重排和低水平受体激活。温度门控暂态 受体电位通道(Thermo TRPs)是一类受温度激活的离子通道。 瞬时受体潜能Melastatin 8(TRPM8)，也称为冷和薄荷醇受体1 (CMR1)，是一种受冷刺激和各种降温试剂控制的非选择性阳离子通道 包括薄荷脑、桉树油醇和冰心素。在初步研究中，我们发现血小板表达 TRPM8和加入TRPM8激动剂模拟典型的形态和功能变化 暴露在寒冷中的血小板。 这些研究的首要目标是描述分子途径的特征 血小板会对温度变化做出反应。进一步阐明这些机制可能会导致 改善了4℃下的血小板输注储存条件，更安全的抗血小板治疗，更好 预防心脏病发作，并在治疗性降低身体时减少副作用 需要心脏骤停后的体温。 在这项提案的目标1中，我们将表征TRPM8在血小板中的作用并阐明其 针对寒冷的血小板表型的特殊功能。这一目标建议在我们初步的基础上扩大 确认人类血小板上的TRPM8的数据，并强调其功能相关性。在AIM 2 我们将评估TRPM8作为一个目标，以抑制在4℃的血小板储存期间使用一个小的 分子TRPM8抑制剂。在本提案的目标3中，我们将确定TRPM8的作用 4℃保存期间的抑制对健康人输血后的恢复、存活和功能的影响 人类受试者。

PROJECT SUMMARY The detection of temperature change by nerve receptors in human tissues is a life‐preserving function which is highly evolutionarily selected. Platelets show a unique response to cold with cytoskeletal rearrangement and low‐level receptor activation. Temperature‐gated transient receptor potential channels (Thermo TRPs) are a family of ion channels activated by temperature. Transient Receptor Potential Melastatin 8 (TRPM8) also known as Cold and Menthol Receptor 1 (CMR1), is a nonselective cation channel gated by cold‐stimuli and various cooling reagents including menthol, eucalyptol, and icilin. In preliminary studies, we show that platelets express TRPM8, and the addition of TRPM8 agonists mimic typical morphologic and functional changes of platelets exposed to cold. The overarching goal of these studies is to characterize the molecular pathways through which platelets react to temperature changes. Further elucidating these mechanisms could lead to improved platelet storage conditions at 4ºC for transfusions, safer antiplatelet therapy, better prevention of heart attacks, and fewer side effects when therapeutic lowering of the body temperature after cardiac arrest is required. In aim 1 of this proposal, we will characterize the role of TRPM8 in platelets and elucidate its specific function for the cold platelet phenotype. This aim proposes to expand on our preliminary data that identified TRPM8 on human platelets and underscore its functional relevance. In aim 2 we will evaluate TRPM8 as a target for inhibition during platelet storage at 4ºC utilizing a small molecule TRPM8 inhibitor. In aim 3 of this proposal, we will determine the role of TRPM8 inhibition during 4ºC storage for recovery, survival, and function after transfusion in healthy human subjects.