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(申请人提供)：急性肾损伤(AKI)是一个主要的健康负担，没有FDA批准的药物来预防或治疗它。目前AKI成功治疗的障碍包括药物的非靶点效应、某些治疗的侵袭性、缺乏合适的AKI动物模型以及对AKI的病理生理学认识不完全。虽然我们对AKI的细胞和分子机制有很大的了解，但对AKI的综合生物学理解在我们的知识中仍然是一个关键的缺口。最近，我们报道了一种基于超声(US)的简单方案，该方案可以减少小鼠的组织和全身炎症，并防止缺血再灌注损伤(IRI)。这种作用依赖于脾和功能性α7烟碱型乙酰胆碱受体(α7nAChRs)，这与US激活脾胆碱能抗炎途径的假设一致。我们的研究表明，US的保护作用依赖于完整的脾、T细胞和骨髓来源的α7nAChRs的存在以及脾的神经支配。最后，US在3种AKI模型上具有保护作用：1)大鼠IRI模型，2)脓毒症大鼠模型，3)AKI(对比-IRI)猪模型。这些结果表明，CAP在调节AKI方面很重要，根据FDA指南中的参数，简单、非侵入性、非药理学地应用US可能会保护肾脏免受AKI的影响。我们建议检验这样的假设：1)脾神经支配代表了AKI中脾的快速神经免疫反应的关键界面；2)FDA指南中非侵入性使用脉冲US通过激活脾CAP来保护肾脏免受AKI的影响。据此我们推测：1)脉冲超声可减轻3种AKI模型(啮齿类动物IRI、脓毒症和猪AKI)的损伤；2)脾胆碱能抗炎通路(CAP)的近端激活与US对AKI的保护作用有关；3)脉冲超声在脾CAP内的细胞机制介导了脉冲超声的组织保护作用。我们的研究将利用包括超声和光遗传学在内的最先进的免疫学和生物力学工程方法，整合a)充分描述宿主对应激、CAP和肾脏损伤的反应的机制，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，以提供必要的工具来更好地理解以前未被认识的应激反应神经控制的概念，这有助于AKI的综合性质，并将提供c)潜在的重要的新的非药物治疗AKI。我们的研究将确定最佳的US特征，以展示保护肾脏免受IRI的生物力学效应，从机械上定义CAP对AKI的保护作用，通过一种独特的光遗传学方法特异性刺激或沉默脾神经，并建立US在相关疾病中的疗效 包括小鼠IRI和败血症AKI以及猪AKI在内的AKI模型使其能够过渡到临床 在人体上进行试验。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。