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.
This mid-career award will ensure that Dr. Fontenot has adequate resources and protected time to train, mentor and support the career development of fellows, junior faculty and other trainees in patient-oriented research in beryllium-induced disease. The research pan will use blood and lung specimens from human subjects with an occupational lung disorder to further our understanding of the beryllium-induced immune mechanisms, hopefully leading to advances in the welfare of this patient population.
|McKee, Amy S; Fontenot, Andrew P (2016) Interplay of innate and adaptive immunity in metal-induced hypersensitivity. Curr Opin Immunol 42:25-30|
|Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7|
|Neff, C Preston; Chain, Jennifer L; MaWhinney, Samantha et al. (2015) Lymphocytic alveolitis is associated with the accumulation of functionally impaired HIV-specific T cells in the lung of antiretroviral therapy-naive subjects. Am J Respir Crit Care Med 191:464-73|
|Bowerman, Natalie A; Falta, Michael T; Mack, Douglas G et al. (2014) Identification of multiple public TCR repertoires in chronic beryllium disease. J Immunol 192:4571-80|
|Lozupone, Catherine; Cota-Gomez, Adela; Palmer, Brent E et al. (2013) Widespread colonization of the lung by Tropheryma whipplei in HIV infection. Am J Respir Crit Care Med 187:1110-7|
|Falta, Michael T; Pinilla, Clemencia; Mack, Douglas G et al. (2013) Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. J Exp Med 210:1403-18|
|Dai, Shaodong; Falta, Michael T; Bowerman, Natalie A et al. (2013) T cell recognition of beryllium. Curr Opin Immunol 25:775-80|
|Chain, Jennifer L; Martin, Allison K; Mack, Douglas G et al. (2013) Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation. J Immunol 191:1648-56|
|Maier, Lisa A; Barkes, Briana Q; Mroz, Margaret et al. (2012) Infliximab therapy modulates an antigen-specific immune response in chronic beryllium disease. Respir Med 106:1810-3|
|Menezes, C A S; Sullivan, A K; Falta, M T et al. (2012) Highly conserved CDR3 region in circulating CD4(+)VÎ²5(+) T cells may be associated with cytotoxic activity in Chagas disease. Clin Exp Immunol 169:109-18|
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