Effect of Pulsed Splenic Ultrasound on delaying Chronic Kidney Disease Progression through a Neuroimmune Mechanism.

PROJECT SUMMARY Chronic Kidney Disease (CKD), a progressive condition that affects over 10% of the population, has emerged as one of the leading causes of mortality worldwide. Episodes of acute kidney injury (AKI) may predispose patients to progression to CKD. Although pharmaceutical agents are continually being developed for CKD, most have only limited efficacy and there are considerable side effects. Furthermore, there are few therapies that can reduce post-injury fibrosis after established AKI. There is a continuing need to develop novel and innovative strategies for the prevention of AKI and importantly, the subsequent transition to CKD. Pulsed ultrasound (pUS), a non-pharmacological noninvasive technology, has substantial potential to meet this need. There has been a growing body of literature demonstrating the ability of ultrasound energy to modulate cells and activate neural circuits. Furthermore, preclinical studies have utilized ultrasound to target immune cells within the spleen to reduce inflammation in both acute and chronic models. Controlling inflammation by neuroimmune modulation may lead to new therapeutic modalities for CKD that are effective after established injury. Prior studies from our lab demonstrated a protective effect of non-targeted ultrasound in preventing ischemic AKI and that this was dependent upon the cholinergic anti-inflammatory pathway (CAP). Preliminary data presented here demonstrates that pUS targeted to the spleen reduces inflammation and protects against toxin induced AKI. Our hypothesis is that therapeutic US can be applied after injury to reduce fibrosis and delay the progression of CKD through activation of the CAP. In Aim 1, I will optimize a pUS regimen to delay the progression of CKD and determine whether there is a therapeutic window of intervention. In Aim 2, I will take a mechanistic approach to understand the effect of ultrasound on the CAP. Specifically, I will determine whether the protective effect of US is due to activating the splenic nerve or due to a direct effect on splenocytes. Furthermore, I will characterize the phenotypic changes in immune cells of the spleen and kidneys after pUS. This proposal involves scientific, professional, and clinical training. Research will be carried out under the guidance of kidney disease expert, Dr. Mark Okusa, ultrasound experts including Dr. John Hossack and Dr. Jonathan Lindner, and immunology expert, Dr. Timothy Bullock, at the University of Virginia. This research will involve additional collaborations and guidance from investigators in the fields of neuroscience and immunology. In addition to providing a potential impactful clinical solution for CKD, this proposal offers a significant training opportunity. Throughout the course of the fellowship, I will have the opportunity to 1) acquire skills in multiple experimental techniques 2) develop a strong knowledge base in kidney disease research 3) receive expert training and guidance in an emerging novel technology 4) learn to communicate my findings to a variety of audiences and 5) foster connections with the nephrology clinical community.