Modulation of peripheral nerve activity as a nonpharmacological, neuroimmumodulatory approach for heart failure, obesity, epilepsy, inflammation, diabetes, bronchoconstriction (forming the basis of anticholinergic treatment of chronic obstructive pulmonary disease), migraines and others and has also been used in hypertension (renal denervation). Despite demonstrated efficacy, optimal therapeutic approaches and a precise understanding of the underlying mechanisms, continue to remain elusive. Moreover most devices are invasive often requiring surgical procedures. Thus, a noninvasive method to modulate peripheral nerve activity could provide an organ protection has targeted innovative approach to understanding neuroimmunomodulation. Over the last few years, we have concentrated our efforts on the use of focused, pulsed ultrasound to protect kidneys from acute kidney injury (AKI), a major health burden with no major pharmacological advances in its prevention or treatment. We reported a simple ultrasound (US)-based protocol that reduced tissue and systemic inflammation and prevented ischemia-reperfusion injury (IRI) in mice by activating the cholinergic anti-inflammatory pathway (CAP). This reflex neuro-immune pathway is a critical juncture in sensing inflammation through its afferent pathway and transmitting anti-inflammatory cues through activation of an efferent pathway (the splenic CAP) thereby preserving peripheral organ function. There are several limitations to our prior approach: i) the use of a human scale clinical ultrasound probe, ii) the inability to target speciic tissues because of the inappropriate probe dimensions, iii) the highly restricted range of ultrasonic focusing / pulsing parameters. The currently available parameters were chosen to address a narrow range of studies in a completely different clinical / experimental context and this limitation precludes any chance of arriving at optimal parameters for controlling mouse AKI. This multi-PI proposal seeks to leverage the strength of expertise in ultrasound technology (scanner operation, beamshaping and transducer design) and animal models of AKI to develop and validate a dual function ultrasound probe to dissect mechanisms of neuroimmunomodulation with greatly improved resolution. Our new high-versatility, dual function, ultrasound probe will be tailored to have the capability of capturing real-time images immediately before or after the application of therapeutic energy to control neural activity and organ function. We plan to test this device in a well-described inflammatory model of AKI, which can be attenuated through pulsed ultrasound that activates the CAP. Results from our tests in AKI may have significant implications in other diseases such as rheumatoid arthritis, colitis, pancreatitis, myocardial infarction to name a few, and the transducer has broad functionality for examining neuroimmunomodulatory mechanisms in these other diseases.
Kidney disease, and in particular acute kidney injury (AKI), is a major economic and public health burden in the United States and world wide with ever increasing rates of hospitalization and unacceptably high mortality (40- 60%) in critically ill patients. Furthermore, AKI may predispose patients to progression to chronic kidney disease and end stage renal disease and ultimately shortened lifespan. The development of effective treatments for AKI is urgently needed and depends on a precise understanding of the molecular, cellular and immunological basis of AKI. The major goal of the current proposal is to develop a highly improved technology that uses sound waves (ultrasound) in combination with tissue imaging to further investigate the underlying mechanisms of a nonpharmacological, noninvasive, ultrasound-based method that we have shown to protect kidneys from AKI.
| Tanaka, Shinji; Okusa, Mark D (2018) Optogenetics in Understanding Mechanisms of Acute Kidney Injury. Nephron 140:152-155 |
| Abe, Chikara; Inoue, Tsuyoshi; Inglis, Mabel A et al. (2017) C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat Neurosci 20:700-707 |
| Tanaka, Shinji; Inoue, Tsuyoshi; Hossack, John A et al. (2017) Nonpharmacological, Biomechanical Approaches to Control Inflammation in Acute Kidney Injury. Nephron 137:277-281 |
| Okusa, Mark D; Rosin, Diane L; Tracey, Kevin J (2017) Targeting neural reflex circuits in immunity to treat kidney disease. Nat Rev Nephrol 13:669-680 |
| Inoue, Tsuyoshi; Abe, Chikara; Sung, Sun-Sang J et al. (2016) Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through ?7nAChR+ splenocytes. J Clin Invest 126:1939-52 |
| Inoue, Tsuyoshi; Okusa, Mark D (2015) Neuroimmune Control of Acute Kidney Injury and Inflammation. Nephron 131:97-101 |
