Mid-Career Investigator Award: Preventing and Diagnosing Fungal Disease

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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.