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) 是免疫功能低下患者死亡的一个严重原因，特别是那些患有癌症、糖尿病和 HIV/AIDS 或接受实体器官或造血干细胞移植的患者（Ascioglu 等人，2002 年） ；科尼利，2008）。在过去的几十年里，由于具有潜在危险因素的患者数量持续增加，IA 的发生率有所增加。值得注意的是，曲霉菌。约占真菌感染总数的 15%，高危人群的死亡率超过 80-90%（Walsh 等，2008）。当真菌负荷相对较低时进行早期治疗对于 IMI 的结果可能至关重要。由于临床症状不明确并且可用的可靠诊断工具不足，因此立即、确定地检测 IA 仍然是一个难题。因此，新的诊断方法代表了未满足且紧迫的医疗保健需求。真菌生物标志物有可能有助于 IA 诊断和治疗监测，并为感染部位的抗真菌治疗提供靶点。我们已经发表了研究，描述了选择性相互作用配体的生物淘选和快速分析 (BRASIL) 方法及其在鉴定与曲霉菌丝和分生孢子结合的肽方面的实用性（Giordano 等人，2001 年；Lionakis 等人，2005 年）。最近，我们通过将金 (Au) 纳米颗粒直接组装到噬菌体上，利用噬菌体颗粒的纳米尺寸作为分子网络，将基于噬菌体展示的靶向扩展到纳米技术应用（Souza 等人，2006a）。我们生成了稳定且具有生物活性的直接组装金噬菌体网络网络，并具有独特且可调节的化学和物理特性。这种调节能力与噬菌体的编程靶向相结合，可以将多种功能集成到单个纳米组件中。我们预计，靶向 Au 噬菌体网络或标记的相应靶向肽将成为 IA 诊断和治疗监测的可靠图像平台。我们的建议是围绕使用靶向噬菌体 Au 纳米颗粒分子网络或标记的靶向肽来诊断 iA。我们的长期目标是开发一种针对 IA 和其他侵袭性真菌感染的高灵敏度成像诊断方法。为此，我们将开发一个用于诊断 IA 的成像平台，在侵袭性曲霉菌病动物模型中验证该平台，并列举其药代动力学特性和毒性以指导临床前研究。 公共卫生相关性：侵袭性曲霉病是免疫抑制的白血病患者和移植受者发病和死亡的常见原因。早期诊断对于改善曲霉菌病的不良预后至关重要。在这里，我们建议使用噬菌体作为基于金（Au）纳米颗粒的成像的靶向部分来诊断真菌感染。