Mid-Career Investigator Award: Preventing and Diagnosing Fungal Disease

描述（由申请人提供）：以患者为导向的研究（POR）提供了直接影响患者护理和结果的机会。年轻的调查人员需要接受正确开展POR的培训。这项建议为指导年轻学员设计和进行POR提供了受保护的时间，以实现特定的研究目标。侵袭性真菌感染（IFIs）的发病率在过去三十年中急剧增加，并且经历实体器官和造血干细胞移植（HSCT）的患者处于这些通常致命的感染的高风险中。缺乏敏感、快速的检测方法来帮助IFIs的早期诊断，导致了高死亡率。开发一种可靠的IFIs早期诊断检测方法将有助于在感染阶段进行治疗，更适合治疗。此外，如果抗真菌治疗方案可以安全地给予发展IFI的高风险患者，并且可以预防感染而不诱导耐药性的发展，那么移植领域将大大受益。因此，本提案的具体研究目的是：1）评估用于预防高危移植人群中IFIs的新预防方案，2）确定易患IFIs的遗传决定因素，从而区分最能从抗真菌预防中获益的移植受者，3）评估用于快速诊断高危人群中IFIs的新实验室检测方法。这些目标将通过由我或我的学员设计和进行的一系列临床研究来实现。预防：将通过一项多中心、随机试验确定吸入性阿朴霉素B脂质复合物（ABLC）在同种异体HSCT人群中的疗效。雾化ABLC可以提供针对真菌疾病的保护，同时避免与全身给药相关的毒性。易感性的遗传决定因素：将在移植受者中研究在小鼠模型中发现的导致侵袭性曲霉病（IA）易感性的基因，以研究其在人类对IA易感性中的作用。新型诊断：将确定在肺移植和儿科HSCT受者中使用葡聚糖测定进行系列监测的性能特征和诊断价值。目前正在开发的用于诊断念珠菌血症的实时PCR检测试剂盒将优化用于临床实验室，并将在移植人群中评估PCR检测试剂盒系列监测的临床效用。

DESCRIPTION (provided by applicant): Patient-oriented research (POR) offers the opportunity to directly impact patient care and outcomes. Young investigators need training in the proper conduct of POR. This proposal provides protected time for mentoring young trainees in the design and conduct of POR in order to address specific research aims. The incidence of invasive fungal infections (IFIs) has increased dramatically over the past thirty years, and patients undergoing solid organ and hematopoietic stem cell transplantation (HSCT) are at high risk for these often lethal infections. The lack of sensitive, rapid tests to aid in early diagnosis of IFIs contributes to the high mortality. Development of a reliable early diagnostic assay for IFIs would facilitate treatment at a stage of infection more amenable to therapy. Furthermore, if an antifungal regimen could be safely given to patients at high risk for developing IFI and could prevent infection without inducing the development of resistance, the field of transplantation would benefit greatly. Therefore, the specific research aims of this proposal are to 1) assess new prophylactic regimens for prevention of IFIs in high risk transplant populations, 2) identify genetic determinants that predispose to IFIs and thereby distinguish transplant recipients who would most benefit from antifungal prophylaxis, and 3) assess new laboratory assays for rapid diagnosis of IFIs in high risk populations. These aims will be met through a series of clinical investigations designed and conducted by me or my trainees. Prophylaxis: Efficacy of inhaled amphotericin B lipid complex (ABLC) will be determined in the allogeneic HSCT population through a multicenter, randomized trial. Aerosolized ABLC may provide protection against fungal disease while avoiding toxicity associated with systemic administration. Genetic Determinants of Susceptibility: Genes found to contribute to invasive aspergillosis (IA) susceptibility in a murine model will be studied in transplant recipients to investigate their role in human susceptibility to IA. Novel Diagnostics: Performance characteristics and the diagnostic value of serial monitoring with the glucan assay in lung transplant and pediatric HSCT recipients will be determined. A realtime PCR assay for diagnosis of candidemia currently under development will be optimized for use in the clinical laboratory and the clinical utility of serial monitoring with the PCR assay will be assessed in transplant populations.