Role of TRPM8 in Cold-stored Platelet Transfusions

项目摘要 通过人体组织中的神经受体检测温度变化是一种维持生命的方法。 这是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。温度门控瞬态 受体电位通道（ThermoTRP）是由温度激活的离子通道家族。 瞬时受体电位Melastatin 8（TRPM 8），也称为冷和月经激素受体1 CMR1是一种非选择性阳离子通道，由冷刺激和各种冷却试剂门控 包括薄荷醇、桉树脑和icilin。在初步研究中，我们发现血小板表达 TRPM8，以及TRPM8激动剂的加入模拟典型的形态和功能变化 血小板暴露在寒冷中。 这些研究的首要目标是表征分子途径， 血小板对温度变化有反应。进一步阐明这些机制可能导致 改善血小板在4ºC下的输血储存条件，更安全的抗血小板治疗，更好的 预防心脏病发作，当治疗降低身体时副作用较少 心脏骤停后的体温。 在本提案的目标1中，我们将描述TRPM 8在血小板中的作用，并阐明其在血小板中的作用。 冷血小板表型的特异性功能。这一目标建议扩大我们的初步 这些数据鉴定了人血小板上的TRPM8，并强调了其功能相关性。在aim 2中 我们将利用小的荧光探针在4ºC血小板储存期间评估TRPM 8作为抑制靶点。 分子TRPM8抑制剂。在本提案的目标3中，我们将确定TRPM的作用8 在4ºC储存期间对健康受试者输血后恢复、存活和功能的抑制 人类实验对象

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.