Ultrasound for Non-Invasive Prevention of Acute Kidney Injury

超声非侵入性预防急性肾损伤

• 批准号: 9028889
• 负责人: Mark Douglas Okusa
• 金额: $ 48.36万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028889
• 关键词: Acetylcholine; Acute Renal Failure with Renal Papillary Necrosis; Address; Adrenergic Receptor; Affect; Agonist; Animal Model; Animals; Anti-Cholinergics; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Attenuated; B-Lymphocytes; Binding; Biological; Biomechanics; Biomedical Engineering; Bone Marrow; Bronchoconstriction; Bungarotoxins; Cell membrane; Cells; Characteristics; Chemicals; Choline O-Acetyltransferase; Chronic Kidney Failure; Chronic Obstructive Airway Disease; Clinical Trials; Colitis; Critical Illness; Denervation; Development; Diabetes Mellitus; Distal; Economics; End stage renal failure; Epilepsy; FDA approved; Family suidae; Functional disorder; Goals; Guidelines; Health; Heart failure; Hospitalization; Human; Hypertension; Immune; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Injury; Kidney; Kidney Diseases; Knowledge; Lead; Light; Link; Longevity; Mediating; Memory; Methods; Migraine; Modeling; Molecular; Morphology; Mus; Myocardial Ischemia; Nature; Nerve; Neurons; Neuropharmacology; Nicotinic Receptors; Norepinephrine; Obesity; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Population; Prevention; Process; Proteins; Protocols documentation; Public Health; Reflex action; Reperfusion Injury; Reporting; Rodent; Rodent Model; Sepsis; Spleen; Splenectomy; Splenocyte; Stress; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Translating; Ultrasonography; United States; attenuation; base; biological adaptation to stress; biomechanical engineering; cholinergic; cytisine; effective therapy; macrophage; monocyte; mortality; nerve supply; neurophysiology; neuroregulation; noradrenergic; novel; optogenetics; prevent; professor; protective effect; public health relevance; renal ischemia; research study; septic; therapeutic target; tool

 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.

 描述（由申请人提供）：急性肾损伤 (AKI) 是一种重大的健康负担，目前尚无 FDA 批准的药物用于预防或治疗。目前成功治疗 AKI 的障碍包括药物的脱靶影响、某些疗法的侵入性、缺乏适当的 AKI 动物模型以及对 AKI 病理生理学的不完全了解。尽管我们对 AKI 的细胞和分子机制有了深入的了解，但对 AKI 的综合生物学理解仍然是我们知识中的一个关键差距。最近，我们报道了一种基于超声 (US) 的简单方案，可减少小鼠的组织和全身炎症并预防缺血再灌注损伤 (IRI)。这种作用依赖于脾脏和功能性 α7 烟碱乙酰胆碱受体 (α7nAChR)，与 US 激活脾胆碱能抗炎途径 (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 细胞和骨髓来源的 α7nAChR 的存在以及脾神经支配。最后，US 对 3 种 AKI 模型具有保护作用：1）IRI 啮齿动物模型，2）败血症啮齿动物模型和 3）AKI 猪模型（对比 IRI）。这些结果表明 CAP 在调节 AKI 方面非常重要，并且使用 FDA 指南中的参数对 US 进行简单的非侵入性、非药理学应用可能会保护肾脏免受 AKI 的影响。我们建议检验以下假设：1) 脾脏的脾神经神经支配是 AKI 中脾脏快速神经免疫反应的关键界面，2) FDA 指南中脉冲超声的无创使用可通过激活脾 CAP 来保护肾脏免受 AKI 的影响。因此，我们假设：目标 1) 脉冲超声将减轻 3 种 AKI 模型（啮齿动物 IRI 和败血症和猪 AKI）的损伤，目标 2) 脾胆碱能抗炎通路 (CAP) 的近端激活与超声在 AKI 中的保护作用存在因果关系，目标 3) 脾 CAP 内的细胞机制介导组织保护作用 脉冲超声波。我们的研究将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）整合宿主对应激、CAP 和肾损伤反应的明确机制，以及 b）生物医学工程、神经生理学和神经药理学的专业知识，以提供必要的工具，以更好地理解以前未被认识的应激反应的神经控制概念，该概念有助于应激反应的综合性质。 AKI 并将为 AKI 提供 c) 一种潜在重要的新型非药物疗法。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，通过独特的光遗传学方法特异性刺激或沉默脾神经支配，从机制上定义 CAP 对 AKI 保护的贡献，并确定 US 在相关方面的功效 AKI 模型，包括小鼠 IRI 和脓毒性 AKI 以及猪 AKI，以便能够过渡到临床 人体试验。概念和治疗原则可能与败血症、结肠炎、心肌缺血和关节炎有关。