Role of TRPM8 in Cold-stored Platelet Transfusions

TRPM8 在冷藏血小板输注中的作用

• 批准号: 10034869
• 负责人: Moritz Stolla
• 金额: $ 50.73万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10034869
• 关键词: Affect; Agonist; Aspirin; Autologous; Biological Assay; Bleeding time procedure; Blood Cells; Blood Circulation; Blood Platelets; Body Temperature; Calcium Signaling; Cations; Clinical; Cryopreservation; Data; Detection; Environment; Eucalyptol; Exposure to; Family; Generations; Genetic; Goals; Growth; Heart Arrest; Hemostatic function; Human; In Vitro; Incubated; Integrins; Ion Channel; Lead; Life; Lipids; Mediating; Membrane; Menthol; Molecular; Morphology; Mus; Myocardial Infarction; Nerve; Nervous system structure; Pathway interactions; Patients; Pharmacology; Phase I Clinical Trials; Platelet Activation; Platelet Transfusion; Platelet aggregation; Prevention; Public Health; Radiolabeled; Reagent; Receptor Activation; Recovery; Risk; Role; Safety; Sepsis; Stimulus; TRP channel; Temperature; Therapeutic; Thrombelastography; Thrombin; Thrombosis; Time; Tissues; Transfusion; Vent; afferent nerve; clopidogrel; cold temperature; human subject; human tissue; icilin; improved; in vitro Assay; in vivo; individual response; inhibitor/antagonist; mouse model; natural hypothermia; novel strategies; platelet function; platelet phenotype; platelet storage; preservation; prevent; receptor; response; sensor; side effect; small molecule

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.

项目概要 通过人体组织中的神经受体检测温度变化是一种保命手段 血小板具有高度进化选择的功能，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。 受体电位通道（Thermo TRP）是由温度激活的离子通道家族。 瞬时受体电位褪黑激素 8 (TRPM8) 也称为冷和薄荷醇受体 1 (CMR1)，是一个由冷刺激和各种冷却试剂门控的非选择性阳离子通道 包括薄荷醇、桉油精和西林 在初步研究中，我们表明血小板表达。 TRPM8 以及 TRPM8 激动剂的添加模拟了典型的形态和功能变化 血小板暴露于寒冷。 这些研究的首要目标是表征分子途径 血小板对温度变化的反应可能会导致这些机制的进一步阐明。 改善输血用 4°C 血小板储存条件，抗血小板治疗更安全，效果更好 预防心脏病发作，并减少治疗性降低身体时的副作用 心脏骤停后需要测量体温。 在本提案的目标 1 中，我们将描述 TRPM8 在血小板中的作用并阐明其作用 冷血小板表型的特定功能 这一目标旨在扩展我们的初步研究。 数据确定了人类血小板上的 TRPM8 并强调了其在目标 2 中的功能相关性。 我们将评估 TRPM8 作为血小板在 4°C 储存期间的抑制靶标，利用一个小 TRPM8 分子抑制剂。在该提案的目标 3 中，我们将确定 TRPM8 的作用。 4°C 储存期间的抑制作用，有助于健康人输血后的恢复、存活和功能 人类受试者。