Mid-Career Investigator Award: Preventing and Diagnosing Fungal Disease

描述(由申请者提供)：以患者为中心的研究(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在POR的适当行为方面进行培训。这一建议为指导年轻受训人员设计和实施POR提供了受保护的时间，以解决具体的研究目标。侵袭性真菌感染(IFIs)的发病率在过去30年里急剧上升，而接受实体器官和造血干细胞移植(HSCT)的患者面临着这些通常是致命的感染的高风险。缺乏灵敏、快速的检测来帮助早期诊断IFIS是导致高死亡率的原因之一。开发一种可靠的IFIS早期诊断方法将有助于在感染阶段更易于治疗的阶段进行治疗。此外，如果一种抗真菌方案能够安全地用于IFI的高危患者，并且能够在不引起耐药性发展的情况下预防感染，移植领域将受益匪浅。因此，这项建议的具体研究目标是：1)评估预防高危移植人群IFI的新预防方案；2)识别易患IFI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；以及3)评估快速诊断高危人群IFI的新的实验室检测方法。这些目标将通过我或我的学员设计和进行的一系列临床调查来实现。预防：将通过多中心随机试验确定吸入两性霉素B脂质复合体(ABLC)在异基因造血干细胞移植人群中的疗效。雾化ABLC可以提供对真菌疾病的保护，同时避免与全身给药相关的毒性。易感性的遗传决定因素：在小鼠模型中发现的导致侵袭性曲霉病(IA)易感性的基因将在移植受者中进行研究，以探讨它们在人类对IA易感性中的作用。新诊断：将确定在肺移植和儿童HSCT受者中使用葡聚糖连续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聚合酶链式反应分析方法将被优化用于临床实验室，并将在移植人群中评估用聚合酶链式反应分析进行连续监测的临床实用性。

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.