Patient-Oriented Research in Beryllium-Induced Disease

描述（由申请人提供）：这个拟议的中期职业奖的总体目标是提高Fontenot博士在肉芽肿性肺病，特别是铍诱发疾病的患者导向研究中培训，指导和支持研究员，初级教师和其他学员的职业发展的能力。这项提议将确保丰特诺特博士有足够的保护时间，为教学和指导研究员、初级教员和其他学员提供更多的机会。此外，这段受保护的时间将允许Fontenot博士参加课程作业，这将提高他的能力，将他的发现转化为改善铍诱发疾病患者的生活质量。慢性铍病（CBD）是一种以肉芽肿性炎症和CD4+ T细胞肺泡炎为特征的职业性肺病。由于其独特的化学和物理性质，铍继续被用于高科技行业，有超过100万美国工人接触过铍，并有患病的风险。由于存在已知抗原和可及的靶器官，CBD是免疫介导的器官破坏的重要模型。我们和其他人已经证明了HLA-DP2在CBD的遗传易感性和铍对致病性CD4+ T细胞的呈现中的重要性。利用人类受试者的血液和支气管肺泡灌洗，本研究计划的目标是阐明铍特异性CD4+ T细胞在HLA-DP2环境下识别铍的机制，并证明铍特异性记忆T细胞池的稳定性。这些研究的发现可能确定高风险受试者疾病进展的潜在生物标志物，以及阻断铍与抗原呈递细胞表面HLA-DP2分子结合的治疗方式。这个项目建立在Fontenot博士最近更新的R01上，该R01研究了致病性T细胞在铍诱导疾病中的作用。指导计划将扩大方特诺特博士在指导医生科学家和其他以患者为导向的研究的受训者方面的作用。此外，研究和指导计划将利用科罗拉多大学和国家犹太健康中心现有的资源和基础设施，包括科罗拉多临床和转化科学研究所的临床科学项目和K12项目，一个在成功培训医生和科学家方面有着长期记录的杰出肺科，以及在基础免疫学和面向患者的研究之间建立桥梁的长期合作。改善CBD患者的生活质量。在这一奖项的支持下，Fontenot博士将成为转化肺免疫学研究的领导者，并培养下一代肺医学的内科科学家。

DESCRIPTION (provided by applicant): The overall goal of this proposed mid-career award is to enhance Dr. Fontenot's ability to train, mentor and support the career development of fellows, junior faculty and other trainees in patient-oriented research in granulomatous lung disease, in particular beryllium-induced disease. This proposal will insure that Dr. Fontenot has adequate protected time to provide more opportunities for teaching and mentoring fellows, junior faculty and other trainees. In addition, this protected time will allow Dr. Fontenot to participate in coursework that will enhance his ability translate his findings toward improving the quality of life of subjects with beryllium-induced disease. Chronic beryllium disease (CBD) is an occupational lung disease that is characterized by granulomatous inflammation and a CD4+ T cell alveolitis. Due to its unique chemical and physical properties, beryllium continues to be utilized in high-technology industries, with more than 1,000,000 US workers having been exposed to beryllium and at risk for disease development. With the presence of a known antigen and an accessible target organ, CBD is an important model of immune-mediated, organ destruction. We and others have shown the importance of HLA-DP2 in the genetic susceptibility of CBD and in the presentation of beryllium to pathogenic CD4+ T cells. Using blood and bronchoalveolar lavage from human subjects, the goals of the research plan are to elucidate the mechanism by which beryllium-specific CD4+ T cells recognize beryllium in the context of HLA-DP2 and to demonstrate the stability of the beryllium-specific memory T cell pool. Findings from these studies may identify potential biomarkers of disease progression in high-risk subjects as well as therapeutic modalities that block beryllium binding to HLA-DP2 molecules on the surface of antigen presenting cells. This program builds on Dr. Fontenot's recently renewed R01 investigating the role of pathogenic T cells in beryllium-induced disease. The mentoring plan will expand Dr. Fontenot's role in mentoring physician-scientists and other trainees in patient-oriented research. In addition, the research and mentoring plan will leverage the resources and infrastructure present at the University of Colorado and National Jewish Health, including the Clinical Science Program and K12 Program in the Colorado Clinical and Translational Sciences Institute, an outstanding Pulmonary Division with a long track record for successfully training physician-scientists, and long-standing collaborations that bridge basic immunology and patient oriented research, to improve the quality of life of CBD patients. With the support of this award, Dr. Fontenot will become a leader in translational lung immunology research and train the next generation of physician scientists in pulmonary medicine.