The unifying goals of this POI competing renewal resubmission are to further understand the immune, exposure, and genetic basis of chronic beryllium disease (CBD) and to discover and validate biological markers of disease, prognosis, and therapeutic response. We hypothesize that antigen-induced granulomatous diseases result from an aberrant interplay between genetic susceptibility and exposure, resulting in immunologic and inflammatory consequences. CBD is a model human disorder in which to advance our understanding of antigen sensitization and granulomatous inflammation. Exposure to beryllium continues as a public health concern with approximately one million individuals currently at risk for developing chronic beryllium disease (CBD). In the past five years, this POI has solidified a productive collaborative team at the University of Colorado and National Jewish Health, establishing a large available patient cohort and all of the needed genetic, immunologic, biochemical, and analytic models, technologies and collaborations to 1) identify the beryllium-peptide antigen, 2) establish the genetic basis of disease susceptibility in relation to environmental exposure, 3) establish the immune basis for disease progression and therapeutic response, and 4) develop new clinical biomarkers based on that understanding. This Program proposal is comprised of three Projects with interdisciplinary translational research approaches and three Cores, as previously. Project 1 will determine the structure of the beryllium-peptide antigen, define how HLA-DP plus antigen trigger the beryllium-reactive T cell antigen receptor response, and use the peptides to pilot a new class of disease biomarkers. Utilizing genome-wide association tools and exposure characterization. Project 2 will establish susceptibility factors underlying antigen presentation and immune pathways relevant to sensitization and disease, along with gene-environment interactions, in a collaboration that combines cohorts from three major beryllium research centers. Project 3 will define the immune regulatory mechanisms involved in the progression from beryllium sensitization to disease, evaluate biomarkers that predict risk of progression from sensitization and disease in beryllium-exposed cohorts and observe effects of pharmacologic intervention. The Projects rely on an Administrative Core, a Clinical and Laboratory Core to provide clinical data and specimens, and a Biostatistics/Exposure Core for data management, analysis and exposure assessment. These findings will have important implications for public health and will be applicable to beryllium-exposed individuals and those with other granulomatous diseases. This proposal will define and validate biological markers of disease risk, progression, and prognosis, identify immune pathways in granulomatous disease, and contribute to the understanding of genetic and environmental variation relevant to immune and inflammatory mechanisms in environmental illness. BACKGROUND This is the first revision of a competitive renewal application for a program project to continue studies into immune mechanisms of chronic beryllium disease directed by Dr. Lee Newman. The application consists of three research projects and three support cores. Productivity: Studies from the first round of funding have resulted in 50 peer-reviewed publications that also covers a period with a minimal level of bridge funding from NIEHS to support the cohort. The productivity and continuance demonstrate quality, commitment and ability to work together. PROGRAM AS INTERGRATED EFFORT

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES011810-09
Application #
8307971
Study Section
Special Emphasis Panel (ZES1-TN-J (ND))
Program Officer
Nadadur, Srikanth
Project Start
2002-09-12
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$1,582,314
Indirect Cost
$252,304
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42
Mack, Douglas G; Falta, Michael T; McKee, Amy S et al. (2014) Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc Natl Acad Sci U S A 111:8553-8
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
Dai, Shaodong; Falta, Michael T; Bowerman, Natalie A et al. (2013) T cell recognition of beryllium. Curr Opin Immunol 25:775-80
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
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
Newman, Kira L; Newman, Lee S (2012) Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol 12:145-50
Van Dyke, Michael V; Martyny, John W; Mroz, Margaret M et al. (2011) Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry. Occup Environ Med 68:842-8
Martin, Allison K; Mack, Douglas G; Falta, Michael T et al. (2011) Beryllium-specific CD4+ T cells in blood as a biomarker of disease progression. J Allergy Clin Immunol 128:1100-6.e1-5
Sawyer, Richard T; Maier, Lisa A (2011) Chronic beryllium disease: an updated model interaction between innate and acquired immunity. Biometals 24:1-17

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