Intrarenal Arteries Sense Trauma-derived Mitochondrial N-formyl Peptides Leading to Kidney Injury in SIRS

肾内动脉感知创伤源性线粒体 N-甲酰肽导致 SIRS 肾损伤

• 批准号: 9333390
• 负责人: Camilla Ferreira Wenceslau
• 金额: $ 8.09万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333390
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Advisory Committees; Affect; Animals; Arteries; Award; Bacteria; Bacterial Infections; Basophils; Biological Markers; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Cardiac; Cause of Death; Cell Communication; Cellular Structures; Cessation of life; Characteristics; Clinical; Clinical Trials; Collaborations; Complication; Data; Development; Diagnosis; Edema; Endothelial Cells; Environment; Enzymes; Extravasation; FPR1 gene; FPR2 gene; Faculty; Femoral vein; Flowmetry; Foundations; Functional disorder; Funding; Future; Germany; Glomerular Filtration Rate; Goals; Growth; Hemorrhagic Shock; Hour; Human; Hyperthermia; Incubated; Infection; Inflammation; Inflammatory Response; Infusion procedures; Injury; Injury to Kidney; Institution; Intensive Care Units; Interlobular Artery; International; Intrinsic factor; Investigative Techniques; Ischemia; Kidney; Kidney Failure; Knockout Mice; Knowledge; Laboratories; Laser-Doppler Flowmetry; Lead; Learning; Leukocytes; Leukocytosis; Leukopenia; Liquid substance; Maintenance; Measurement; Measures; Mediator of activation protein; Mentors; Microscopy; Mitochondria; Modeling; Molecular; Molecular Profiling; Mus; Nephrectomy; Neutrophil Infiltration; Nitric Oxide; Organ; Pathogenesis; Patients; Pattern; Peptides; Perfusion; Pharmacology; Phase; Physiology; Plasma; Play; Positioning Attribute; Prevention; Production; Rattus; Receptor Activation; Renal Blood Flow; Renal Circulation; Renal function; Reperfusion Therapy; Research; Research Personnel; Resistance; Role; Science; Sepsis; Sepsis Syndrome; Source; Sterility; Symptoms; Syndrome; Tachycardia; Technical Expertise; Testing; Therapeutic; Time; Tissues; Training; Translating; Translational Research; Trauma; Trauma patient; Traumatic injury; Ultrasonography; Universities; Vascular Diseases; Vascular System; Vasodilation; Visit; Wistar Rats; base; career; cell injury; common symptom; experience; fMet-Leu-Phe receptor; formyl peptide; glomerular filtration; hemodynamics; immunogenic; improved; in vivo; indexing; kidney vascular structure; meetings; natural hypothermia; neutrophil; novel; novel marker; peptide deformylase; pressure; prevent; programs; protein expression; public health relevance; release factor; renal artery; renal ischemia; response to injury; signal recognition particle receptor; success; tenure track; translational study; two-photon; vasoconstriction

 DESCRIPTION (provided by applicant): Systemic inflammatory response injury (SIRS) and sepsis are the principal causes of death in trauma patients in the USA. The diagnosis of sepsis requires confirmation of bacterial growth in blood cultures, as well as the presence of two or more of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea and leukocytopenia or leukocytosis. However, only about one-third to one half of patients meeting these criteria are subsequently diagnosed with an infection. Accordingly, all remaining patients are diagnosed with SIRS. The major pathophysiological characteristic of SIRS and sepsis is vascular collapse. Breakdown of the endothelial barrier function results in the loss of fluid into the extravascular space and may lead to edema in several tissues, including the kidneys. Therefore, a frequent complication that affects more than 35% of patients with SIRS is the development of acute kidney injury (AKI). There is a lack of knowledge about the pathogenesis of AKI during SIRS, specifically as there is no study showing whether intrarenal arteries play a role in the genesis and/or maintenance of AKI during trauma-induced SIRS. Several studies have proposed that renal vasoconstriction and reduced renal blood flow (RBF) are the major causes of AKI in SIRS. However, recent observations have showed that improvements in cardiac index as well as blood pressure did not result in improved renal function and prevention of death. This implies that poor forward flow alone does not account for the development of AKI. Although it has been well established that AKI is a unifying factor of SIRS and sepsis in trauma patients, a common mediator to the many types of sepsis and SIRS has not been discovered. Also, the mechanism by which traumatic injury leads to SIRS is not fully understood. It has been proposed that cell components from traumatized tissue, called damage-associated molecular patterns (DAMPs), are the primary instigators of SIRS in trauma patients. For evolutionary reasons, mitochondria share several characteristics with bacteria and N-formyl peptides are common molecular signatures of both bacteria and mitochondria. We have observed that mitochondrial N-formyl peptides (F-MIT) induce vascular leakage, exacerbated vasodilatation and inflammation in resistance arteries via formyl peptide receptor activation. In a preliminary study, it was observed for the first time that sterile trauma induces the release of F-MIT into the circulation of patients with SIRS. Also, it was observed that F-MIT leads to SIRS, intrarenal artery dysfunction and kidney injury via FPR activation. Therefore, based on our preliminary data, it is clear that F-MIT plays a role in SIRS. However, it is unclear whether these peptides are responsible for the development of AKI due to intrarenal arteries dysfunction (e.g. exacerbated vasodilatation associated with vascular leakage, inflammation and local edema). We propose the novel and intriguing hypothesis that higher levels of F-MIT in the circulation after trauma/ischemia activate FPR leading to intrarenal artery dysfunction, AKI and SIRS. The objective of this K99/R00 application is to reveal an intrinsic factor released after cell damage initiates SIRS and acute inflammation of intrarenal arteries which results in AKI with or without hemodynamic changes. This application will also facilitate the transition of my research career towards an independent investigator position. The training (K99) phase of this award will be mentored by Dr. Clinton Webb, who is internationally recognized leader in the fields of vascular physiology and will be co- mentored by Dr. Paul O´Connor, who has devoted his career to studying whole animal renal physiology and is an expert in kidney injury. Also, during the mentored phase, I will pursue addition training in the laboratory of Dr. Grisk at University of Greifswald, Germany. It is with Dr. Grisk where I plan to learn in vivo techniques for investigating simultaneous recordings of renal perfusion and I will learn how to isolate human intrarenal arteries. These experiences will play a vital role for the completion of the independent phase of this award. My visit to the Dr. Grisk's laboratory not only will expand my technical skill and experience with different models, but it will also initiate collaboration with an expert in the renal field. Such interaction would expand the scope of my current research and improve the potential for success in gaining further independent funding as I establish my own independent research program. My short- term goal is to become an independent investigator in the field of renal vascular physiology and pathophysiology of trauma and SIRS. As an expert in these fields, I hope to obtain a tenure-track faculty position in an academic institution that promotes interdisciplinary biomedical science and has an emphasis on translational research. My long-term career goal is to establish a strong research program using integrative approaches to study the effects of injury-associated vascular dysfunction on renal physiology.

 描述（由应用提供）：全身炎症反应损伤（SIRS）和败血症是美国创伤患者死亡的主要原因。败血症的诊断需要确认血液培养物中细菌的生长，以及存在以下两个或多种症状：体温过低或高温，心动过速，tachypnea和白细胞减少症或白细胞细胞增多症。但是，符合这些标准的患者中，只有大约三分之一至一半的患者被诊断出感染。根据所有其余患者的诊断为SIRS。 SIRS和败血症的主要病理生理特征是血管塌陷。内皮屏障功能的崩溃导致流体损失到血管外空间中，并可能导致包括肾脏在内的多个组织中的水肿。因此，经常影响超过35％的SIRS患者的并发症是急性肾脏损伤（AKI）的发展。缺乏关于SIRS期间AKI发病机理的知识，特别是因为没有研究表明肾内动脉是否在创伤引起的SIRS期间AKI的起源和/或维持中是否起作用。几项研究表明，肾血管收缩和肾血流减少（RBF）是SIRS中AKI的主要原因。但是，最近的观察结果表明，心脏指数和血压的改善并没有改善肾功能和预防死亡。这意味着仅向前流量较差并不能解释AKI的发展。尽管已经很好地确定AKI是创伤患者的Sir和败血症的统一因素，但尚未发现许多类型的败血症和Sirs的常见介体。同样，创伤性损伤导致SIRS的机制是，已经提出，受创伤组织的细胞成分（称为损伤相关的分子模式（抑制））是创伤患者SIRS的主要启动者。由于进化原因，线粒体与细菌和N-甲胺肽具有多种特征是细菌和线粒体的常见分子特征。我们已经观察到线粒体N-甲基甲基肽（F-MIT）通过甲基胡椒受体激活诱导耐药性动脉中的血管渗漏，加剧的血管舒张和炎症。在一项初步研究中，无菌创伤首次诱导F-MIT释放到该研究中 SIRS患者的循环。同样，观察到F-MIT会导致SIRS，通过FPR激活导致SIRS，肾内动脉功能障碍和肾脏损伤。因此，根据我们的初步数据，很明显，F-MIT在SIRS中起作用。但是，目前尚不清楚这些宠物是否是由于肾内动脉功能障碍引起的AKI的发展（例如，与血管泄漏，炎症和局部水肿相关的加重血管舒张）。我们提出了一种新颖而有趣的假设，即创伤/缺血后循环中较高的F-MIT激活FPR导致肾内动脉功能障碍，AKI和SIRS。该K99/R00应用的目的是揭示细胞损伤引发SIRS和肾内动脉急性炎症后释放的固有因素​​，从而导致AKI有或没有血液动力学变化。该应用程序还将促进我的研究生涯向独立研究者职位的过渡。该奖项的培训阶段（K99）将由克林顿·韦伯（Clinton Webb）博士称为血管生理学领域的国际认可的领导者，并将由Paul O´Connor博士合作，他致力于研究整个动物肾脏生理学，并且是肾脏受伤的专家。此外，在修订阶段，我将在德国格里夫斯瓦尔德大学的固定师实验室进行额外培训。正是在Grisk博士的情况下，我计划学习用于研究肾脏灌注的同时记录的体内技术，我将学习如何隔离人体内动脉。这些经验将对独立的完成起着至关重要的作用 这个奖项的阶段。我对Grisk博士的实验室的访问不仅会扩大我的技术技能和不同模型的经验，而且还将与专家进行合作 肾脏场。当我建立自己的独立研究计划时，这种互动将扩大我当前研究的范围，并提高成功获得进一步独立资金的潜力。我的短期目标是成为创伤和SIRS肾血管生理学和病理生理学领域的独立研究者。作为这些领域的专家，我希望在一个学术机构中获得终身教师职位，该学术机构促进跨学科的生物医学科学，并重点是转化研究。我的长期职业目标是使用综合方法来建立一个强大的研究计划，以研究损伤相关血管功能障碍对肾脏生理的影响。