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: 9340175
• 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/9340175
• 关键词: Acetylcholine; Acute Renal Failure with Renal Papillary Necrosis; Address; Adrenergic alpha-Antagonists; Affect; Agonist; Animal Model; Animals; Anti-Cholinergics; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Attenuated; B-Lymphocytes; Binding; Biological; Biomechanics; Biomedical Engineering; Bone Marrow; Bronchoconstriction; 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; Homeostasis; Hospitalization; Human; Hypertension; Immune response; Immune system; Immunologics; 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; Neuroimmune; Neurons; Neuropharmacology; Norepinephrine; Obesity; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Population; Prevention; Process; Proteins; Protocols documentation; Public Health; Reflex action; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Rodent; Rodent Model; Sepsis; Spleen; Splenectomy; Splenocyte; Stress; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Translating; Ultrasonography; United States; alpha Bungarotoxin; alpha-bungarotoxin receptor; attenuation; base; beta-2 Adrenergic Receptors; biological adaptation to stress; biomechanical engineering; cytisine; effective therapy; experimental study; immunoregulation; macrophage; monocyte; mortality; nerve supply; neurophysiology; neuroregulation; noradrenergic; novel; optogenetics; prevent; professor; protective effect; public health relevance; renal ischemia; response; 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) 是一种主要的健康负担，目前尚无 FDA 批准的药物用于预防或治疗 AKI，目前成功治疗 AKI 的障碍包括药物的脱靶作用、某些药物的侵入性。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，即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 方面很重要，并且美国使用 FDA 内的参数的简单非侵入性、非药物应用指南可以保护肾脏免受 AKI 的影响。提议检验以下假设：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因此，我们追求：目标 1) 脉冲超声将减轻 3 种 AKI 模型（啮齿动物 IRI 和脓毒症以及猪）的损伤。 AKI)，目标 2) 脾胆碱能抗炎通路 (CAP) 的近端激活与 US 在 AKI 中的保护作用存在因果关系，目标 3) 脾 CAP 内的细胞机制介导脉冲超声的组织保护作用。我们的研究将通过最先进的免疫学和生物力学工程方法（包括超声和b) 来自生物医学工程、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神经控制概念，这有助于 AKI 的综合性质，并将提供 c) 一种潜在的重要新颖和我们的研究将确定最佳的 US 特征，以证明保护肾脏免受 IRI 的生物力学作用，机械地定义 CAP 通过以下方式预防 AKI 的贡献：一种独特的光遗传学方法，可特异性刺激或沉默脾神经支配，并确定超声在相关方面的功效 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 人体试验的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。