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Molecular identity of exosomal BK channels

外泌体 BK 通道的分子特性

基本信息

批准号：
10544007
负责人：
Mahmood Khan
金额：
$ 61.83万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-24 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544007
关键词：
Animals Attention Biochemical Biogenesis Biological Brain Hypoxia-Ischemia Calcium Cardiac Cardiac Myocytes Cell Death Cell membrane Cells Cytoplasm Cytoprotection Data Data Analyses Disease Disease Marker Distant Docking Drug Delivery Systems Electrophysiology (science)Environment Face Future Genetic Goals Heart Homeostasis Human Investigation Ion Channel Ion Exchange Ions Link Liposomes Measures Mediator Medicine Membrane Messenger RNA Methods MicroRNAs Mitochondria Molecular Molecular Biology Molecular Target Mus Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Injury Organelles Osmolar Concentration Osmosis Osmotic Shocks Outcome Physiological Physiology Plasma Play Potassium Potassium Channel Process Proteins Proteomics Pump RNA Splicing Reperfusion Injury Reporting Role Signal Transduction Source Stress Techniques Testing Therapeutic Time Tissues Variant Voltage-Gated Potassium Channel Wild Type Mouse biophysical properties body system cardioprotection coronary fibrosis delivery vehicle exosome experimental study extracellular extracellular vesicles gain of function imaging approach in silico induced pluripotent stem cell derived cardiomyocytes innovation intercellular communication large-conductance calcium-activated potassium channels macromolecule molecular imaging mouse model mutant new technology novel patch clamp programs sensor superresolution microscopy targeted delivery therapeutic development therapeutic target transmission process

项目摘要

Abstract Extracellular vesicles (EVs) have gained significant attention since their discovery in 1983 as important mediators of intercellular communications, potential disease markers, therapeutic targets, and drug delivery vehicles. Though it is widely accepted that EVs get packaged inside the cell, pass through the extracellular environment, and deliver the cargo to the target cells. However, even after 37 yrs it is not determined, 1) how EVs handle the differential ionic environment (cytoplasm vs extracellular), 2) whether EVs possess any functional ion channels, and 3) whether any of these channels play a physiological role. We focused on answering these questions and focused on an ion with the largest gradient, i.e., potassium. Using the in silico approach, we discovered several ion channels, and the most prominent ion channels, we discovered in exosomes is BK. We incorporated a novel electrophysiology approach, near field electrophysiology, as canonical patch-clamp methods are not feasible due to the size of exosomes. We discovered that functional BK channels exist in exosomes, and decide the integrity of exosomes. Our preliminary data also indicate that exosomal BK can protect the heart from ischemia-reperfusion injury. We will now test the hypothesis that exosomes containing BK determine the content of exosomes, facilitate their survival in variable ionic environments, and protect the heart from IR injury. Overall the data supports the above hypothesis which will be tested using multiple approaches and pursuing the following specific aims to, 1. establish a presence, molecular identity, and biophysical properties of BK in exosomes, 2. determine the physiological role of BK in exosomes., and 3. elucidate the mechanistic role of exosomal BK channels in cardioprotection. In our proposal, we have incorporated genetic mice models, and innovative as well as a novel technology to understand a very basic and broad biological question. The outcome of this program will open an opportunity to study exosomal ion channels including BK channels, and advance the exosome field by determining how exosome survive variable osmolarities, establishing the molecular identity of exosomal ion channels, understand how cargo content is regulated by exosomal ion channels, and the role and mechanism of exosomal ion channels in cardioprotection. In the future, our study will set the ground for exploring other ion channels in exosomes from different living beings as well as organ systems.

摘要