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Intrarenal Arteries Sense N-formyl Peptides Leading to Vascular Injury in Sepsis

肾内动脉感知 N-甲酰肽导致脓毒症血管损伤

基本信息

批准号：
10450907
负责人：
Camilla Ferreira Wenceslau
金额：
$ 5.94万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
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：
2016-09-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450907
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 Endothelium 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 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 Source Sterility Symptoms Syndrome Systemic Inflammatory Response 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 hospital readmission immunogenic improved in vivo indexing kidney dysfunction 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 systemic inflammatory response tenure track translational study two photon microscopy vascular injury vasoconstriction

项目摘要

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（由申请人提供）：全身炎症反应损伤（SIRS）和脓毒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培养中的细菌生长，以及是否存在以下两种或多种症状：体温过低或体温过高、心动过速、呼吸急促和白细胞减少或白细胞增多。然而，符合这些标准的患者中只有约三分之一到一半随后被诊断为感染。因此，所有剩余患者均被诊断为 SIRS。 SIRS和脓毒症的主要病理生理学特征是血管塌陷。内皮屏障功能的破坏导致液体流失到血管外空间，并可能导致包括肾脏在内的多种组织水肿。因此，影响超过 35% SIRS 患者的常见并发症是急性肾损伤 (AKI)。目前对 SIRS 期间 AKI 的发病机制缺乏了解，特别是没有研究表明肾内动脉是否在创伤诱发的 SIRS 期间 AKI 的发生和/或维持中发挥作用。多项研究提出，肾血管收缩和肾血流量 (RBF) 减少是 SIRS 中 AKI 的主要原因。然而，最近的观察表明，心脏指数和血压的改善并不能改善肾功能和预防死亡。这意味着仅前向血流不良并不能解释 AKI 的发生。尽管已明确 AKI 是创伤患者 SIRS 和脓毒症的统一因素，但尚未发现多种类型脓毒症和 SIRS 的共同介导因素。此外，创伤性损伤导致 SIRS 的机制尚不完全清楚。有人提出，来自创伤组织的细胞成分，称为损伤相关分子模式（DAMP），是创伤患者发生 SIRS 的主要诱因。出于进化原因，线粒体与细菌具有一些共同特征，N-甲酰肽是细菌和线粒体的共同分子特征。我们观察到线粒体 N-甲酰基肽 (F-MIT) 通过甲酰基肽受体激活诱导血管渗漏、加剧血管舒张和阻力动脉炎症。在一项初步研究中，首次观察到无菌创伤诱导 F-MIT 释放到 SIRS 患者的循环。此外，还观察到 F-MIT 通过 FPR 激活导致 SIRS、肾内动脉功能障碍和肾损伤。因此，根据我们的初步数据，很明显 F-MIT 在 SIRS 中发挥着作用。然而，尚不清楚这些肽是否与肾内动脉功能障碍（例如与血管渗漏、炎症和局部水肿相关的血管舒张加剧）导致 AKI 的发生有关。我们提出了一个新颖且有趣的假设，即创伤/缺血后循环中较高水平的 F-MIT 会激活 FPR，导致肾内动脉功能障碍、AKI 和 SIRS。 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内在因子，从而导致伴有或不伴有血流动力学变化的 AKI。该申请还将促进我的研究生涯向独立研究者职位的转变。该奖项的培训（K99）阶段将由国际公认的血管生理学领域领军人物Clinton Webb博士指导，并由致力于研究整个动物肾脏生理学、肾损伤专家的Paul O´Connor博士共同指导。此外，在指导阶段，我将在德国格赖夫斯瓦尔德大学 Grisk 博士的实验室接受额外的培训。我计划与 Grisk 博士一起学习研究肾灌注同时记录的体内技术，并且我将学习如何分离人肾内动脉。这些经验对于完成独立自主的工作将起到至关重要的作用。本奖项的阶段。我对 Grisk 博士实验室的访问不仅将扩展我在不同模型方面的技术技能和经验，而且还将启动与该领域专家的合作肾野。这种互动将扩大我当前的研究范围，并在我建立自己的独立研究计划时提高获得进一步独立资助的成功潜力。我的短期目标是成为肾血管生理学以及创伤和 SIRS 病理生理学领域的独立研究者。作为这些领域的专家，我希望在促进跨学科生物医学科学并重视转化研究的学术机构中获得终身教职。我的长期职业目标是建立一个强大的研究计划，采用综合方法来研究损伤相关的血管功能障碍对肾脏生理的影响。