Novel Clinical Diagnostic Targets For Detection of Invasive Mold Aspergillosis

检测侵袭性霉菌曲霉病的新临床诊断目标

• 批准号: 8077208
• 负责人: WADIH ARAP
• 金额: $ 19.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077208
• 关键词: AIDS/HIV problem; Accounting; Affinity; Amphotericin B; Animal Model; Antifungal Agents; Antifungal Therapy; Aspergillosis; Aspergillus; Aspergillus fumigatus; Azoles; Bacteriophages; Binding; Biodistribution; Biological Markers; Cell Surface Receptors; Clinical; Confocal Microscopy; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Imaging; Diagnostic Procedure; Disease; Dose; Drug Kinetics; Early Diagnosis; Early treatment; Generations; Goals; Gold; Healthcare; Hematopoietic stem cells; Hyphae; Image; Immunocompromised Host; Infection; Investigation; Label; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Methodology; Methods; Molds; Molecular; Monitor; Morbidity - disease rate; Mycoses; Nanotechnology; Organ; Outcome; Patients; Peptides; Phage Display; Pilot Projects; Predisposition; Property; Publishing; Risk Factors; Schedule; Site; Solid; Stem cell transplant; Surface; Symptoms; System; Therapeutic Uses; Time Study; Toxic effect; Tracer; Transplant Recipients; base; cancer imaging; chemical property; high risk; improved; in vivo; leukemia; mortality; mouse model; nanoassembly; nanoparticle; novel; novel diagnostics; particle; pathogen; physical property; preclinical study; programs; public health relevance; receptor; standard care; success; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is a serious cause of mortality in immunocompromised patients, particularly those suffering from cancer, diabetes and HIV/AIDS or undergoing solid-organ or hematopoietic stem cell transplant (Ascioglu et al., 2002; Cornely, 2008). The occurrence of IA heightened over the past couple of decades because the number of patients with underlying risk factors continues to increase. Noteworthy, Aspergillus sp. account for approximately 15% of total fungal infections with a mortality that exceeds 80-90% in high risk groups (Walsh et al., 2008). Early treatment when the fungal burden is relatively low could be critical for the outcome of IMI. Immediate and conclusive detection of IA remains a conundrum since clinical symptoms are ambiguous and insufficient reliable diagnostic tools are available. Therefore, new diagnostic methods represent an unmet and pressing healthcare need. Fungal biomarkers have the potential to contribute to IA diagnosis and treatment monitoring as well as provide targets for antifungal therapy delivery to the site of infection. We have already published studies describing the Biopanning and Rapid Analysis of Selective Interacting Ligands (BRASIL) method and its utility in identification of peptides binding to Aspergillus hyphae and conidia (Giordano et al., 2001; Lionakis et al., 2005). More recently, we have expanded phage display- based targeting to nanotechnology applications through the direct-assembly of gold (Au) nanoparticles onto phage, exploiting the nanodimensions of the phage particle as a molecular network (Souza et al., 2006a). We generated stable and biologically active networks of direct-assembled Au-phage networks with concomitant unique and tunable chemical and physical properties. This tuning capability combined with the programmed targeting of the phage affords the integration of multiple functionalities into a single nanoassembly. We envision that either targeted Au-phage networks or labeled corresponding targeted peptides will become a reliable image platform for IA diagnosis and treatment monitoring. Our proposal is framed around the use of targeting phage Au nanoparticle molecular networks or labeled targeted peptides to diagnose iA. Our long-term goal is to develop a highly sensitive imaging diagnostic methodology for IA and other invasive fungal infections. To that end, will develop an imaging platform for diagnosis of IA, validate this platform in an animal model of invasive aspergillosis and enumerate its pharmacokinetical properties and toxicity to guide pre-clinical studies. PUBLIC HEALTH RELEVANCE: Invasive aspergillosis is a common cause of morbidity and mortality in immunosuppressed patients with leukemia and transplant recipients. Early diagnosis is of critical importance in improving the poor outcome of aspergillosis. Here we propose to use phage as targeting moieties for Gold (Au) nanoparticles based imaging for fungal infection diagnosis.

描述（由申请人提供）：侵袭性曲霉病（IA）是免疫副不动的患者死亡率的严重原因，尤其是患有癌症，糖尿病和HIV/AIDS的患者，或经历固体器官或造血干细胞移植的患者（Ascioglu等人，2002年； Cornely，2008）。在过去的几十年中，IA的发生增加，因为具有潜在危险因素的患者数量不断增加。值得注意的是，曲霉sp。在高风险组中，死亡率超过80-90％（Walsh等，2008），约占真菌总感染的15％。当真菌负担相对较低时，早期治疗对于IMI的结果至关重要。由于临床症状模棱两可，并且可靠的可靠诊断工具不足，因此对IA的直接和结论性检测仍然是一个难题。因此，新的诊断方法代表了一种未满足和紧迫的医疗保健需求。真菌生物标志物有可能为IA诊断和治疗监测做出贡献，并为抗真菌治疗的靶标提供到感染部位的靶标。我们已经发表了描述选择性相互作用配体（BRASIL）方法的生物固定和快速分析的研究及其在鉴定肽结合与曲霉菌丝和分生孢子结合的肽方面的实用性（Giordano等，2001; Lionakis et al。，2005）。最近，我们通过金（AU）纳米颗粒的直接组装将基于噬菌体显示的靶向扩展到纳米技术应用到噬菌体，从而利用了噬菌体粒子作为分子网络的纳米二含量（Souza等，2006a）。我们建立了具有独特且可调化的化学和物理特性的直接组装Au-Phage网络的稳定和生物活性网络。这种调整能力与噬菌体的编程靶向相结合，可以将多个功能整合到单个纳米组件中。我们设想有针对性的Au-PAGE网络或标记为相应的靶向肽将成为IA诊断和治疗监测的可靠图像平台。我们的建议是围绕靶向噬菌体Au纳米颗粒分子网络或标记为靶向肽诊断IA的靶向的建议。我们的长期目标是为IA和其他侵入性真菌感染开发高度敏感的成像诊断方法。为此，将开发一个用于诊断IA的成像平台，在侵入性曲霉菌病动物模型中验证该平台，并列举其药物动力学特性和毒性，以指导临床前研究。 公共卫生相关性：侵入性曲霉菌病是免疫抑制性白血病和移植受者的发病率和死亡率的常见原因。早期诊断对于改善曲霉病的不良结果至关重要。在这里，我们建议将噬菌体用作基于金（AU）纳米颗粒的基于真菌感染诊断的成像的靶向部分。