Mid-Career Investigator Award: Preventing and Diagnosing Fungal Disease

职业生涯中期研究员奖：预防和诊断真菌病

• 批准号: 7623517
• 负责人: BARBARA D ALEXANDER
• 金额: $ 11.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623517
• 关键词: Address; Allogenic; Amphotericin B-Lipid Complex; Antifungal Agents; Aspergillosis; Award; Biological Assay; Breathing; Characteristics; Childhood; Clinical; Clinical Research; Clinical Trials; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Genetic Determinism; Glucans; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Incidence; Infection; Infection prevention; Laboratories; Lung; Mentors; Modeling; Monitor; Multicenter Trials; Mus; Mycoses; Organ; Outcome; Patient Care; Patients; Performance; Population; Predisposition; Prophylactic treatment; Randomized Controlled Clinical Trials; Research; Research Institute; Research Personnel; Resistance development; Role; Series; Site; Solid; Staging; Stem cell transplant; Susceptibility Gene; Testing; Time; Toxic effect; Training; Transplant Recipients; Transplantation; Treatment Protocols; aerosolized; candidemia; career; design; high risk; innovation; meetings; mortality; novel diagnostics; patient oriented research; prevent; prophylactic; rapid diagnosis

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.

描述（由申请人提供）：面向患者的研究（POR）提供了直接影响患者护理和结果的机会。年轻的研究人员需要在适当行为的情况下进行培训。该建议为指导年轻学员的设计和行为提供了受保护的时间，以解决特定的研究目标。在过去的三十年中，侵入性真菌感染（IFIS）的发病率急剧增加，患有固体器官和造血干细胞移植（HSCT）的患者对这些经常致命的感染有高风险。缺乏敏感，快速的测试以帮助早期诊断IFI会导致高死亡率。开发可靠的IFI的早期诊断测定法将在感染阶段促进治疗，更适合治疗。此外，如果可以安全地将抗真菌疗法安全地给予患有高风险的IFI风险，并且可以防止感染而不诱导抗药性发展，则移植领域将受到极大的影响。因此，该提案的具体研究目的是1）评估预防高风险移植人群中IFI的新的预防性方案，2）确定易感IFI的遗传决定因素，从而区分移植者，从而区分最大程度地从抗真菌预防中受益的移植者，以及3）评估新的实验室测定法，以快速诊断高风险人群中的IFI。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：通过多中心，随机试验，将在同种异体HSCT种群中确定吸入两性霉素B脂质复合物（ABLC）的功效。雾化的ABLC可以提供防止真菌疾病的保护，同时避免与全身给药相关的毒性。易感性的遗传决定因素：发现在鼠模型中有助于侵袭性曲霉病（IA）易感性的基因将在移植受者中研究，以研究其在人类对IA易感性中的作用。新型诊断：将确定肺移植和小儿HSCT受体中葡聚糖测定法的性能特征和诊断值。将在临床实验室中优化用于诊断目前正在开发的候选血症的实时PCR分析，并将在移植人群中评估使用PCR测定的串行监测的临床实用性。