The goal of this proposal is the advanced training of Dr. Loren Denlinger to complete his transition from a basic scientist to an academic clinical investigator in airway diseases. The long range Career Goal is to become an independently funded clinical investigator with local and national leadership potential, focusing on airway disorders linked epidemiologically to respiratory pathogens, and with a view towards personalized- medicine for the diagnosis and treatment of these infections. The Objectives for this proposal are to 1) become practically familiar with the skills needed for asthma phenotyping, 2) utilize epidemiological methods to translate basic science findings to clinical research hypotheses, and 3) develop project management, leadership, and business skills. The Career Development plan proposes a combination of new didactic courses, workshops, and practicum experiences, taking advantage of the established infrastructure in needs assessment, development planning and evaluation of the University of Wisconsin Clinical Investigator Preparatory Program. The Mentoring Committee has been restructured to include new intellectual influences to shape Dr. Denlinger's clinical research skills development, and a detailed plan with each mentor synchronizing training activities. This will take place within the rich environment provided by the University of Wisconsin and the NHLBI Asthma Clinical Research Center. The scientific focus is on the host-specific variability in the immune response to intracellular respiratory pathogens that contribute to the acute and chronic pathophysiology of asthma. Generally stated, the hypothesis is that the nucleotide receptor P2X7 is part of a set of innate immune factors important to the acute and chronic clearance of intracellular pathogens. Ancillary protocols to the Sponsor and Co-Sponsor's grant and clinical trial provide the means to test a functional screening tool for P2X7 activity within epidemiological databases and assess its role as a risk factor in both acute and chronic asthma. Pharmacogenomic analysis of the P2X7 responses of primary alveolar macrophages will also be performed with an eye toward risk factor modification in future clinical trials. In lay-language summary, this proposal will promote high-level training of a new clinical investigator interested in developing new patient-specific therapies for asthma, a condition affecting 7% of the U.S. population with an increasing prevalance and morbidity.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (O1))
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Rothgeb, Ann E
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Manthei, D M; Schwantes, E A; Mathur, S K et al. (2014) Nasal lavage VEGF and TNF-? levels during a natural cold predict asthma exacerbations. Clin Exp Allergy 44:1484-93
Denlinger, Loren C; Kelly, Elizabeth A B; Dodge, Ann M et al. (2013) Safety of and cellular response to segmental bronchoprovocation in allergic asthma. PLoS One 8:e51963
Denlinger, Loren C; Manthei, David M; Seibold, Max A et al. (2013) P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy. Am J Respir Crit Care Med 187:28-33
Manthei, David M; Jackson, Daniel J; Evans, Michael D et al. (2012) Protection from asthma in a high-risk birth cohort by attenuated P2X(7) function. J Allergy Clin Immunol 130:496-502
Shi, Lei; Manthei, David M; Guadarrama, Arturo G et al. (2012) Rhinovirus-induced IL-1? release from bronchial epithelial cells is independent of functional P2X7. Am J Respir Cell Mol Biol 47:363-71
Denlinger, Loren C; Sorkness, Ron L; Lee, Wai-Ming et al. (2011) Lower airway rhinovirus burden and the seasonal risk of asthma exacerbation. Am J Respir Crit Care Med 184:1007-14
Guilbert, Theresa W; Denlinger, Loren C (2010) Role of infection in the development and exacerbation of asthma. Expert Rev Respir Med 4:71-83
Denlinger, Loren C; Shi, Lei; Guadarrama, Arturo et al. (2009) Attenuated P2X7 pore function as a risk factor for virus-induced loss of asthma control. Am J Respir Crit Care Med 179:265-70