R01HL157453

Molecular Identity of Exosomal BK Channels - 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, it is still not determined, after 37 years, how EVs handle the differential ionic environment (cytoplasm vs extracellular), whether EVs possess any functional ion channels, and 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:

1. Establish a presence, molecular identity, and biophysical properties of BK in exosomes.
2. Determine the physiological role of BK in exosomes.
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 exosomes survive variable osmolarities, establishing the molecular identity of exosomal ion channels, understanding 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.

Ohio State University

THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS; FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS; AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Columbus, Ohio 432101239 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $626,209 to $3,028,194.