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Role of TRPM8 in Cold-stored Platelet Transfusions

TRPM8 在冷藏血小板输注中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结