Tailoring ultrasound technology to explore mechanisms of activation of the splenic neuroimmune axis in attenuating acute organ injury.

 描述(申请人提供)：调节周围神经活动，作为治疗心力衰竭、肥胖、癫痫、炎症、糖尿病、支气管收缩(构成慢性阻塞性肺疾病抗胆碱能治疗的基础)、偏头痛和其他疾病的非药物、神经免疫方法，还被用于高血压(肾脏去神经)。尽管已证明有效，但最佳治疗方法和对潜在机制的准确理解仍然难以捉摸。此外，大多数设备都是侵入性的，通常需要外科手术。因此，一种非侵入性的调节周围神经活动的方法可以提供有针对性的器官保护，为理解神经免疫调节提供了一种创新的方法。在过去的几年里，我们一直致力于使用聚焦脉冲超声来保护肾脏免受急性肾损伤(AKI)的影响，AKI是一种主要的健康负担，在预防或治疗方面没有重大的药理学进展。我们报道了一种基于超声(US)的简单方案，该方案通过激活胆碱能抗炎途径(CAP)来减少小鼠的组织和全身炎症，并防止缺血再灌注损伤(IRI)。这种反射性神经免疫途径是通过其传入途径感知炎症并通过激活传出途径(脾CAP)传递抗炎信号从而保护外周器官功能的关键节点。我们以前的方法有几个限制：i)使用人体尺寸的临床超声探头，ii)由于探头尺寸不合适而无法瞄准特定组织，iii)超声聚焦/脉冲参数的高度限制范围。目前可用的参数是为了解决在完全不同的临床/实验环境中进行的一系列狭窄的研究，这种限制排除了任何获得控制小鼠AKI的最佳参数的机会。这一多PI方案寻求利用AKI在超声技术(扫描仪操作、波束整形和换能器设计)和动物模型方面的专业知识来开发和验证双功能超声探头，以极大地提高分辨率来剖析神经免疫调节机制。我们的新型多功能、双功能超声探头将经过量身定制，能够在施加治疗能量之前或之后立即捕获实时图像，以控制神经活动和器官功能。我们计划在AKI的炎症模型中测试这种设备，这种炎症模型可以通过激活CAP的脉冲超声波来减弱。我们对AKI的测试结果可能对其他疾病，如类风湿性关节炎、结肠炎、胰腺炎、心肌梗死等具有重要意义，并且该传感器具有广泛的功能，可用于检测这些其他疾病的神经免疫调节机制。

 DESCRIPTION (provided by applicant): 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.