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Tailoring ultrasound technology to explore mechanisms of activation of the splenic neuroimmune axis in attenuating acute organ injury.

定制超声技术探索脾神经免疫轴激活减轻急性器官损伤的机制。

基本信息

批准号：
9341636
负责人：
John A Hossack
金额：
$ 5.68万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9341636
关键词：
Acoustics Acute Acute Renal Failure with Renal Papillary Necrosis Address Afferent Pathways Animal Model Animals Anti-Cholinergics Anti-Inflammatory Agents Anti-inflammatory Area Atherosclerosis Attenuated Bronchoconstriction Characteristics Chronic Kidney Failure Chronic Obstructive Airway Disease Clinical Colitis Critical Illness Critical Pathways Cues Data Denervation Development Devices Diabetes Mellitus Dimensions Disease Economics Efferent Pathways Electronics End stage renal failure Epilepsy Family suidae Focused Ultrasound Frequencies Goals Health Heart Heart failure Hospitalization Human Hypertension Image Immune In Vitro Inflammation Inflammatory Injury Ischemia Kidney Kidney Diseases Ligation Liver Longevity Lung Maintenance Mechanics Mediating Methods Migraine Modality Modeling Molecular Mus Myocardial Infarction Names Nerve Nerve Regeneration Neuroimmunomodulation Neurons Norepinephrine Obesity Operative Surgical Procedures Organ Output Pancreatitis Pathway interactions Patients Peripheral Peripheral Nerves Physiologic pulse Prevention Protocols documentation Public Health Puncture procedure Reflex action Reperfusion Injury Reperfusion Therapy Reporting Research Research Personnel Resolution Rheumatoid Arthritis Rodent Sepsis Sequoia Series Specificity Spleen T-Lymphocyte Technology Testing Therapeutic Time Tissue imaging Tissues Transducers Ultrasonic wave Ultrasonics Ultrasonography United States Vagus nerve structure Variant alpha-bungarotoxin receptor base cholinergic design effective therapy improved in vivo indexing innovation interest mortality neuroregulation novel operation prevent programs protective effect relating to nervous system renal ischemia sound tool

项目摘要

DESCRIPTION (provided by applicant): Modulation of peripheral nerve activity as a nonpharmacological, neuroimmumodulatory approach for heart failure, obesity, epilepsy, inflammation, diabetes, bronchoconstriction (forming the basis of anticholinergic treatment of chronic obstructive pulmonary disease), migraines and others and has also been used in hypertension (renal denervation). Despite demonstrated efficacy, optimal therapeutic approaches and a precise understanding of the underlying mechanisms, continue to remain elusive. Moreover most devices are invasive often requiring surgical procedures. Thus, a noninvasive method to modulate peripheral nerve activity could provide an organ protection has targeted innovative approach to understanding neuroimmunomodulation. Over the last few years, we have concentrated our efforts on the use of focused, pulsed ultrasound to protect kidneys from acute kidney injury (AKI), a major health burden with no major pharmacological advances in its prevention or treatment. We reported a simple ultrasound (US)-based protocol that reduced tissue and systemic inflammation and prevented ischemia-reperfusion injury (IRI) in mice by activating the cholinergic anti-inflammatory pathway (CAP). This reflex neuro-immune pathway is a critical juncture in sensing inflammation through its afferent pathway and transmitting anti-inflammatory cues through activation of an efferent pathway (the splenic CAP) thereby preserving peripheral organ function. There are several limitations to our prior approach: i) the use of a human scale clinical ultrasound probe, ii) the inability to target speciic tissues because of the inappropriate probe dimensions, iii) the highly restricted range of ultrasonic focusing / pulsing parameters. The currently available parameters were chosen to address a narrow range of studies in a completely different clinical / experimental context and this limitation precludes any chance of arriving at optimal parameters for controlling mouse AKI. This multi-PI proposal seeks to leverage the strength of expertise in ultrasound technology (scanner operation, beamshaping and transducer design) and animal models of AKI to develop and validate a dual function ultrasound probe to dissect mechanisms of neuroimmunomodulation with greatly improved resolution. Our new high-versatility, dual function, ultrasound probe will be tailored to have the capability of capturing real-time images immediately before or after the application of therapeutic energy to control neural activity and organ function. We plan to test this device in a well-described inflammatory model of AKI, which can be attenuated through pulsed ultrasound that activates the CAP. Results from our tests in AKI may have significant implications in other diseases such as rheumatoid arthritis, colitis, pancreatitis, myocardial infarction to name a few, and the transducer has broad functionality for examining neuroimmunomodulatory mechanisms in these other diseases.

描述（由申请人提供）：调节周围神经活动作为一种非药物、神经免疫调节方法，用于治疗心力衰竭、肥胖、癫痫、炎症、糖尿病、支气管收缩（构成慢性阻塞性肺病抗胆碱能治疗的基础）、偏头痛等，也已用于高血压（肾去神经术）。尽管已证明疗效，但最佳治疗方法和对潜在机制的精确理解仍然难以捉摸。此外，大多数设备都是侵入性的，通常需要进行外科手术。因此，调节周围神经活动的非侵入性方法可以提供器官保护，为理解神经免疫调节提供了有针对性的创新方法。在过去的几年里，我们集中精力使用聚焦脉冲超声来保护肾脏免受急性肾损伤（AKI）的影响，这是一种重大的健康负担，但在预防或治疗方面没有重大的药理学进展。我们报道了一种基于超声（US）的简单方案，该方案通过激活胆碱能抗炎通路（CAP）来减少小鼠组织和全身炎症并预防缺血再灌注损伤（IRI）。这种反射性神经免疫通路是通过传入通路感知炎症并通过激活传出通路（脾 CAP）传递抗炎信号从而保持外周器官功能的关键节点。我们之前的方法有几个限制：i）使用人体规模的临床超声探头，ii）由于探头尺寸不合适而无法瞄准特定组织，iii）超声聚焦/脉冲参数的范围受到高度限制。选择当前可用的参数是为了在完全不同的临床/实验背景下进行小范围的研究，这种限制排除了获得控制小鼠 AKI 的最佳参数的任何机会。该多 PI 提案旨在利用超声技术（扫描仪操作、波束整形和换能器设计）和 AKI 动物模型方面的专业知识来开发和验证双功能超声探头，以大幅提高分辨率来剖析神经免疫调节机制。我们的新型多功能、双功能超声探头将经过定制，能够在应用治疗能量之前或之后立即捕获实时图像，以控制神经活动和器官功能。我们计划在一个已被充分描述的 AKI 炎症模型中测试该装置，该模型可以通过激活 CAP 的脉冲超声来减弱该模型。我们在 AKI 中的测试结果可能对其他疾病（例如类风湿性关节炎、结肠炎、胰腺炎、心肌梗塞等）具有重要意义，并且传感器具有广泛的功能，可用于检查这些其他疾病的神经免疫调节机制。