Ultrasound for Non-Invasive Prevention of Acute Kidney Injury

超声非侵入性预防急性肾损伤

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：急性肾脏损伤（AKI）是一种重大的健康燃烧，没有FDA批准的药物用于预防或治疗。目前成功治疗AKI的障碍包括药物剂的脱靶影响，某些疗法的侵入性性质，缺乏适当的AKI动物模型以及对AKI病理生理学的不完全理解。尽管我们对AKI的细胞和分子机制有深刻的了解，但对AKI的综合生物学理解仍然是我们知识的关键差距。最近，我们报道了一种简单的超声（US）基础方案，该方案减少了组织和全身感染，并防止了小鼠缺血 - 再灌注损伤（IRI）。该作用取决于脾和功能性α7烟碱乙酰胆碱受体（α7NACHRS），这与美国激活脾胆碱能抗炎途径（CAP）的假设一致。我们的研究表明，美国的受保护作用取决于完整的臂，T细胞和骨髓来源的α7NACHR和脾脏神经的存在。最后，在3种AKI模型中保护了美国：1）IRI的啮齿动物模型，2）败血症的啮齿动物模型和3）AKI的猪模型（对比IRI）。这些结果表明，CAP在调节AKI方面很重要，并且使用FDA指南中的参数对美国进行了简单的非侵入性非药物应用可能会保护Kidsneys免受AKI的侵害。我们建议测试以下假设：1）脾脏的脾神经神经支配代表脾脏在AKI中的快速神经免疫反应中的关键界面和2）在FDA指南中无创的脉冲使用我们的脉冲使用，通过激活Splenic Cap来保护儿童免受AKI的保护。根据我们的假设：目标1）脉动我们将在3种AKI模型（啮齿动物IRI和败血症和Pig Aki）中减轻伤害，目标2）脊髓胆碱能抗炎性途径（CAP）的近端激活与US在AKI和AIN中的pul seffers的效应意外相关，并在AKI和AIM中构成了3），并将其与AKI的蛋白质相关联。超声波。我们的研究将整合a）通过使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，以及b）生物医学工程，神经生理学和神经药理学来更好地理解neuroct of neuroct of neuroct的概念，从而使宿主对压力，帽子和肾脏损伤的特征良好的机制，包括对压力，帽和肾脏损伤的良好机制，包括超声和上遗传学的损伤。 AKI并将为AKI提供一种潜在的重要新颖和非药物疗法。我们的研究将定义最佳的美国特征，以证明生物力学效应以保护肾脏免受IRI的影响，从机械上定义了帽子对通过独特的光遗传学方法来保护AKI的贡献，以特异性刺激或沉默的脾脏神经支配，并确定美国在相关性中的有效性小鼠中的AKI模型，包括IRI和化粪池AKI和AKI，猪的AKI可以过渡到临床人类的审判。概念和治疗原理可能与败血症，结肠炎，心肌缺血和关节炎有关。