HIF-1 mediated vascular integrity limits Aspergillus invasion in airway rejection

HIF-1 介导的血管完整性限制曲霉菌入侵气道排斥反应

基本信息

批准号：
9118339
负责人：
Joe L Hsu
金额：
$ 16.8万
依托单位：
STANFORD UNIVERSITY
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：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118339
关键词：
Actins Allografting Angiogenesis Inducing Agents Angiogenesis Inhibitors Aspergillosis Aspergillus Aspergillus fumigatus Attenuated Award Biological Assay Biology Blood Vessels Blood flow Bone Marrow Cell Culture Techniques Cell Hypoxia Cells Cirrhosis Clinical Cytoskeleton Data Development Diffuse Disease Endothelial Cells Epithelial Cells Epithelium Extravasation Flowmetry Fluorescein-5-isothiocyanate Genetic Gliotoxin Goals Growth Health Heme Hemorrhage High Pressure Liquid Chromatography Hypoxia Hypoxia Inducible Factor In Vitro Incidence Infection Injury Integration Host Factors Iron Iron Overload Ischemia Knockout Mice Lectin Life Lung Lung Transplantation Measures Mediating Mediator of activation protein Mentors Microspheres Modeling Modification Molds Molecular Morality Mus Mycoses Nature Organ Transplantation Outcome Oxygen Pathogenesis Pathway interactions Peptide Hydrolases Perfusion Production Reporter Research Risk Risk Factors Role Scientist Signal Transduction Solid Staining method Stains Stimulus Testing The science of Mycology Therapeutic Therapeutic Effect Therapeutic Intervention Thrombosis Tissues Transgenic Organisms Transplant Recipients Transplantation Up-Regulation Vascular Permeabilities Virulence Work attenuation cadherin 5 career effective therapy extracellular heme a hypoxia inducible factor 1 improved in vivo liver transplantation mortality multidisciplinary mutant novel novel therapeutics pathogen prevent repaired research study response restoration transcription factor transcriptome uptake

项目摘要

DESCRIPTION (provided by applicant): This project is a K08 mentored career clinical scientist award that focuses on signals that promote Aspergillus fumigatus invasion, a ubiquitous mould that causes invasive pulmonary aspergillosis (IPA) resulting in >200,000 cases of serious infection yearly. In lung transplants, invasive A. fumigatus infections cause airway anastomotic complications and IPA with a morality rate as high as 80%. Aspergillus establishes and adapts to a severely hypoxic microenvironment by vascular invasion, thrombosis, and the production of antiangiogenic factors, which likely contribute to its virulence. Transplanted lungs are particularly vulnerable to ischemia, as the only solid organ allografts that do not routinely undergo primary systemic arterial restoration during trans- plantation. Thus, ischemia, working in concert with Aspergillus infection is a unique and critical host- pathogen factor. Using a novel murine tracheal transplant model, we found that Aspergillus becomes more deeply invasive as the allograft undergoes progressive rejection-mediated ischemia. Upregulating endothelial hypoxia inducible factor (HIF)-1a (a stimulator of angiogenesis and vascular repair) limited the invasion of the mould. In preliminary studies, we have elucidated a hypothesized role for HIF-1� in repairing microvascular injury, which improves microvascular perfusion and decreases tissue iron overload (from diffuse microvascular hemorrhage, i.e., iron released from heme breakdown), and thus blocks iron overload, a putative stimulus for Aspergillus invasion and a critical substrate for fungal growth. In this proposal, we define HIF-1a as a pivotal mediator for the observed attenuation of Aspergillus invasion. In Specific Aim 1 we focus on the host, as we investigate the effect of modulating host HIF-1a and graft iron overload on Aspergillus invasion. Two subaims evaluate these host factors: Aim 1a: determines how endothelial HIF-1a mitigates Aspergillus invasion, examining the contribution of tissue devitalization and allograft iron overload; and Aim 1b: determines the role of graft iron overload in promoting Aspergillus invasion. For Specific Aim 2, we focus on the pathogen, studying the impact that A. fumigatus has on host microvascular repair, using highly specific angiogenic cell, transgenic murine markers. With successful outcomes of the proposed studies, we anticipate the strong conclusion that A. fumigatus invasion can be modulated by endothelial cell HIF-1a upregulation, which would have significant therapeutic implications in decreasing the risk for Aspergillus-related invasive infections and elucidate fundamental biologic principles underlying A. fumigatus pathogenesis. This result would create the opportunity for greater multidisciplinary collaborative interchange to evaluate underlying signaling mechanisms and the development of novel therapeutic strategies to improve survival after lung transplantation.

描述（由适用提供）：该项目是K08修订的职业临床科学家奖，该奖项的重点是促进曲曲霉的烟曲霉入侵，这是一种无处不在的霉菌，可导致侵入性肺曲霉菌病（IPA），导致每年> 20万例严重感染。在肺移植物中，侵入性烟曲霉感染会导致气道吻合并发症和IPA，道德率高达80％。曲霉建立并适应了通过血管侵袭，血栓形成和抗血管生成因子的产生的严重低氧微环境，这可能会导致其病毒。移植的肺特别容易受到缺血的影响，这是唯一的固体器官外观在跨性植物期间，请勿常规进行原发性的全身动脉恢复。那是缺血，与曲霉感染一起工作是一种独特而关键的宿主病原因子。使用一种新型的鼠气管移植模型，我们发现，随着同种异体移植发生渐进拒绝介导的缺血，曲霉变得更加侵入性。上调内皮缺氧诱导因子（HIF）-1a（血管生成和血管修复的刺激剂）限制了霉菌的侵袭。在初步研究中，我们阐明了HIF-1的假设作用。在修复微血管损伤时，可以改善微血管灌注并减少组织铁的超负荷（从弥漫性微血管出血，即从血红素崩溃中释放的铁），从而阻止铁超负荷，这是曲霉入侵的假定刺激，以及一种关键的底物来进行拟合量。在此提案中，我们定义HIF-1A 作为观察到的曲霉侵入衰减的关键介体。在特定的目标1中，我们关注宿主，当我们研究调节宿主HIF-1A和移植铁超负荷对曲霉侵袭的影响。两个子aim评估了以下宿主因素：目标1a：确定内皮HIF-1A如何减轻曲霉的侵袭，研究组织退化化和同种异体移植铁超负荷的贡献； AIM 1B：确定移植铁超负荷在促进曲霉入侵中的作用。对于特定目标2，我们专注于病原体，研究烟曲霉对宿主微血管修复的影响，使用高度特异性的血管生成细胞转基因鼠标记。通过拟议的研究的成功结果，我们预期有一个强烈的结论，即可以通过内皮细胞HIF-1A上调来调节烟曲霉的侵袭，这将对降低与曲霉相关的浸润性感染的风险和阐明基本生物学原理的风险具有显着的热含义。这一结果将为更大的多学科协作互换创造机会，以评估潜在的信号机制和开发新型的治疗策略，以改善肺移植后的生存。