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

• 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
• 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

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（由申请人提供）：该项目是 K08 指导的职业临床科学家奖，重点关注促进烟曲霉入侵的信号，烟曲霉是一种普遍存在的霉菌，可引起侵袭性肺曲霉病 (IPA)，每年导致超过 200,000 例严重感染病例。在肺移植中，侵袭性烟曲霉感染会导致气道吻合口并发症和IPA，死亡率高达80%。曲霉菌通过血管侵入、血栓形成和抗血管生成因子的产生来建立和适应严重缺氧的微环境，这可能有助于其毒力。 移植的肺特别容易出现缺血，因为这是唯一的同种异体实体器官移植物 移植期间不常规进行初次全身动脉修复。因此，缺血与曲霉菌感染协同作用是一种独特且关键的宿主-病原体因素。使用一种新型的小鼠气管移植模型，我们发现随着同种异体移植物经历进行性排斥介导的缺血，曲霉菌变得更具侵入性。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� 在修复微血管损伤中的假设作用，它改善了微血管灌注并减少了组织铁过载（来自弥漫性微血管出血，即血红素分解释放的铁），从而阻止了铁过载，铁过载是曲霉菌入侵的假定刺激物和真菌生长的关键底物。在本提案中，我们定义了 HIF-1a 作为观察到的曲霉菌入侵减弱的关键介质。在具体目标 1 中，我们重点关注宿主，研究调节宿主 HIF-1a 和移植物铁超载对曲霉菌入侵的影响。两个子目标评估这些宿主因素： 目标 1a：确定内皮 HIF-1a 如何减轻曲霉菌侵袭，检查组织失活和同种异体移植物铁超载的作用；目标 1b：确定移植物铁超载在促进曲霉菌侵袭中的作用。对于具体目标 2，我们重点关注病原体，利用高度特异性的血管生成细胞和转基因小鼠标记物，研究烟曲霉对宿主微血管修复的影响。凭借拟议研究的成功结果，我们预期得出强有力的结论，即烟曲霉入侵可以通过内皮细胞 HIF-1a 上调来调节，这对于降低曲霉相关侵袭性感染的风险具有重要的治疗意义，并阐明烟曲霉发病机制的基本生物学原理。这一结果将为更多的多学科合作交流创造机会，以评估潜在的信号传导机制和开发新的治疗策略，以提高肺移植后的生存率。