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Optical Tools to Study Purinergic Signaling

研究嘌呤能信号传导的光学工具

基本信息

批准号：
10364329
负责人：
Mathew Tantama
金额：
$ 35.57万
依托单位：
WELLESLEY COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364329
关键词：
Acetoacetates Acute Address Affect Affinity Animal Model Astrocytes Biochemical Biological Biosensor Blood Vessels Brain Cell Communication Cell Volumes Cell physiology Cell surface Cells Chemotaxis Chronic Coculture Techniques Communication Complex Coupling Cyclic AMP Disease Drug resistance Elements Energy Metabolism Ensure Event Fasting Genetic Engineering Goals Health Hydroxybutyrates Hyperactivity Image Immune Immune response In Vitro Infection Injury Ketone Bodies Kinetics Knowledge Learning Length Ligands Lipids Long-Term Effects Measurement Measures Mediating Mediator of activation protein Metabolic Metabolism Methods Microglia Mitochondria Molecular Monitor Neuroglia Neurons Nucleotides Optics Organ Organism Pain Pathology Pharmaceutical Preparations Pharmacology Phenotype Physiological Platelet Aggregation Inhibitors Plavix Preparation Protein Engineering Purinergic P1 Receptors Purinoceptor Receptor Activation Regulation Resolution Sampling Seizures Sepsis Series Signal Transduction Specificity Specimen Stroke Structure Surface Synaptic Transmission System Technology Testing Therapeutic Tissues Traumatic Brain Injury Work autocrine brain metabolism brain tissue cell type childhood epilepsy design-build-test effective therapy experimental study extracellular imaging study insight interest ketogenic diet live cell imaging multiplexed imaging nanomolar neural network neuroprotection novel paracrine sensor small molecule success tool virtual

项目摘要

Project Summary/Abstract Extracellular ATP and ADP are mediators of purinergic signaling in cell-to-cell communication in virtually every tissue. Autocrine and paracrine purinergic signaling contributes to normal cellular functions such as immune cell chemotaxis and cell volume regulation, and purinergic signaling also contributes to pathology in injury, infection, sepsis, and a number of diseases. Notably, extracellular ATP and ADP mediate purinergic signaling between cells with both short-term and long-term effects. However, it has been a challenge to study the cellular and molecular mechanisms by which ATP and ADP control distinct signaling events because their levels are spatially heterogeneous and purinergic signaling can vary significantly from cell-to-cell. Clearly, direct measurements of extracellular nucleotides are needed, but current methods are not well adapted to measuring fluctuations in the low extracellular nucleotide concentrations expected in live specimens. To overcome this barrier, we will use protein engineering to develop high affinity cell-surface sensors that can be used to resolve the complex spatial and temporal dynamics of ATP and ADP release, clearance, and purinergic receptor activation. To demonstrate the application of our sensors and also guide their optimization, we will study neuron-glia purinergic signaling in the brain. In particular, we will use our sensors to learn how metabolic state affects the function of microglia, the resident immune cells in the brain, in regulating the regional purinergic dynamics that impact local neuronal activity. The proposed series of multiplexed imaging studies that pair our purinergic sensors with sensors of downstream signaling should directly visualize core elements of neuron-glia purinergic communication in an integrated manner. This should provide valuable insight into novel mechanisms responsible for the coupling between brain energy metabolism and excitability. Furthermore, the genetically-encoded tools developed through this proposal should be broadly applicable to deeper study of any purinergic system.

项目总结/文摘