Ultrasound for Non-Invasive Prevention of Acute Kidney Injury

 描述（由申请人提供）：急性肾损伤（阿基）是一种主要的健康负担，没有FDA批准的药物用于预防或治疗。目前成功治疗阿基的障碍包括药物的脱靶效应、某些治疗的侵入性、缺乏适当的阿基动物模型以及对阿基病理生理学的不完全理解。尽管我们对阿基的细胞和分子机制有着广泛的了解，但对阿基的综合生物学理解仍然是我们知识中的一个关键空白。最近，我们报道了一个简单的超声（US）为基础的协议，减少组织和全身炎症，并防止缺血再灌注损伤（IRI）的小鼠。这种作用依赖于脾脏和功能性α7烟碱乙酰胆碱受体（α 7 nAChRs），与US激活脾脏胆碱能抗炎通路（CAP）的假设一致。我们的研究表明，US的保护作用取决于完整的脾脏、T细胞和骨髓源性α 7 nAChR的存在以及脾脏神经支配。最后，US在3种阿基模型中具有保护作用：1）啮齿动物IRI模型，2）啮齿动物脓毒症模型和3）猪阿基模型（对比剂IRI）。这些结果表明，CAP在调节阿基方面很重要，并且使用FDA指南内的参数进行简单的非侵入性非药理学US应用可能会保护肾脏免受阿基的影响。我们建议检验以下假设：1）脾脏的脾神经神经支配代表阿基中脾脏快速神经免疫反应的关键界面，2）FDA指南中脉冲US的无创使用通过激活脾脏CAP保护肾脏免受阿基影响。因此，我们假设：目的1）脉冲超声将减轻3种阿基模型（啮齿动物IRI和脓毒症以及猪阿基）的损伤，目的2）脾脏胆碱能抗炎通路（CAP）的近端激活与超声在阿基中的保护作用有因果关系，目的3）脾脏CAP内的细胞机制介导脉冲超声的组织保护作用。我们的研究将整合a）宿主对应激反应的良好表征机制，CAP和肾损伤，通过利用最先进的免疫学和生物力学工程方法，包括超声和光遗传学，和B）生物医学工程的专业知识，神经生理学和神经药理学提供必要的工具，以更好地了解以前未被认识的概念，神经控制的压力反应，有助于阿基的整合性质，并将提供c）阿基的潜在重要的新型和非药物疗法。我们的研究将定义最佳的US特征以证明保护肾脏免受IRI的生物力学效应，通过特异性刺激或沉默脾神经支配的独特光遗传学方法从机制上定义CAP对保护免受阿基的贡献，并建立US在相关疾病中的功效。 阿基模型，包括小鼠中的IRI和脓毒性阿基以及猪中的阿基，以能够过渡到临床 人体试验概念和治疗原则可能与脓毒症、结肠炎、心肌缺血和关节炎有关。

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a major health burden with no FDA-approved drugs for its prevention or treatment. Current barriers to successful treatment of AKI include off-target affects of pharmacological agents, invasive nature of certain therapies, the lack of appropriate animal models of AKI and incomplete understanding of the pathophysiology of AKI. Although we have an immense understanding of the cellular and molecular mechanisms of AKI, an integrative biological understanding of AKI remains a critical gap in our knowledge. Recently, we reported a simple ultrasound (US)-based protocol that reduced tissue and systemic inflammation and prevented ischemia-reperfusion injury (IRI) in mice. This effect was dependent on the spleen and functional α7 nicotinic acetylcholine receptors (α7nAChRs), consistent with the hypothesis that US activated the splenic cholinergic anti-inflammatory pathway (CAP). Our studies indicate that the protective effect of US depends on an intact spleen, the presence of T cells and bone marrow-derived α7nAChRs, and splenic innervation. Lastly, US was protective in 3 models of AKI: 1) rodent model of IRI, 2) rodent model of sepsis and 3) pig model of AKI (contrast-IRI). These results suggest that the CAP is important in modulating AKI and that a simple noninvasive, nonpharmacological application of US using parameters within FDA guidelines may protect kidneys from AKI. We propose to test the hypothesis that: 1) splenic nerve innervation of the spleen represents a critical interface in rapid neuro-immune response by the spleen in AKI and 2) a noninvasive use of pulsed US within the FDA guidelines protects kidneys from AKI by activating the splenic CAP. Accordingly we hypothesize that: Aim 1) pulsed US will attenuate injury in 3 models of AKI (rodent IRI and sepsis and pig AKI), Aim 2) proximal activation of the splenic cholinergic anti-inflammatory pathway (CAP) is causally linked to the protective effect of US in AKI, and Aim 3) cellular mechanisms within the splenic CAP mediate the tissue protective effect of pulsed ultrasound. Our studies will integrate a) a well-characterized mechanism of host response to stress, the CAP, and kidney injury by utilizing state-of-the-art immunological and biomechanical engineering methods including ultrasound and optogenetics, and b) expertise from biomedical engineering, neurophysiology and neuropharmacology to provide necessary tools to better understand a previously unrecognized concept of the neural control of the stress response that contributes to the integrative nature of AKI and will provide c) a potentially important novel and nonpharmacological therapy for AKI. Our studies will define the optimal US characteristics to demonstrate a biomechanical effect to protect kidneys from IRI, define mechanistically the contribution of the CAP to protection from AKI through a unique optogenetic approach to specifically stimulate or silence splenic innervation, and establish the efficacy of US in relevant models of AKI including IRI and septic AKI in mice and AKI in pigs to enable transition to clinical trials in humans. Concepts and therapeutic principles could be pertinent to sepsis, colitis, myocardial ischemia, and arthritis.