The prevalence of allergic diseases, including food allergies, eczema, and asthma, has risen over the last quarter century, and these disorders can lead to significant morbidity for affected patients. Mast cells play a central role in the clinical expression of allergic disease, largely by acquiring the capacity to respond to allergens. Though the acute effects of mast cell activation by allergens are well known, the regulation of the acquisition of allergen sensitivity and the contribution of mast cells to chronic allergic inflammation are poorly understood. A basic understanding of these questions will provide new insights into mast cell biology as well as avenues for therapeutic intervention. This career development proposal has two primary goals. First, the candidate outlines a 5-year career development plan to establish an independent research program. Highlights of this plan include mentorship by Dr. Richard Locksley, a committee structured to provide both scientific and career advice during the candidate's progress, didactic coursework, meetings to supplement local opportunities for scientific growth and networking, as well as workshops on laboratory management and professional skills. Second, the candidate outlines a 5-year research strategy to examine fundamental questions related to mast cell biology. Preliminary data indicate that tissue mast cells extend projections into the vascular endothelium as a means to capture IgE and respond to allergen.
Aim 1 will investigate the molecular regulation of this process. The remaining aims will examine the mast cell contribution to chronic allergic inflammation.
Aim 2 will investigate the role of mast cell derived IL-13 in driving Th2 differentiation.
Aim 3 will delineate the hierarchical relationships between allergic immune cells in chronic dermatitis and the timing of the mast cell contribution to this response. The strategic approach will utilize advanced technologies, such as reporter antibody molecules, intravital video microscopy, and mice in which specific subsets of cells (based on lineage or function) can be deleted. The candidate is an MSTP graduate and pediatric allergist-immunologist at the University of California, San Francisco (UCSF). He has a publication record at each stage of his training (undergraduate, doctoral thesis, and postdoctoral fellowship). Though the candidate has a background in immunology, the areas of prior study and techniques employed were distant from his current scientific focus. He would, therefore, benefit from the structured period of mentorship and training outlined in the proposal. After completion of the training period, the candidate will continue to develop an independent research program at an academic medical center with the long-term goal of understanding the contributions of mast cells to health and disease. UCSF provides an ideal environment for the training of pediatric physician-scientists. The UCSF Department of Pediatrics has a long track record of fostering the career development of young faculty. In addition, the UCSF Immunology program has a unique breadth of immunological expertise with a number of investigators who are leaders in their respective fields. In summary, this proposal will foster the continued development of the candidate's clinical and scientific portfolio. Upon completion of the proposal, the candidate will likely have made a number of original contributions to our understanding of mast cells in allergic disease. The candidate will also be positioned to compete for further funding opportunities as he develops an independent research program.

Public Health Relevance

Allergic diseases, including food allergies, eczema, and asthma, have shown a dramatic increase in prevalence over the last two decades. This proposal examines two fundamental questions related to the role of the mast cell in allergic disease. First, how do mast cells acquire the capacity to respond to allergen? Second, how do mast cells influence and shape the immune response after activation?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Transplantation Biology &Immunology-2 (AITC)
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Prograis, Lawrence J
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Cheng, Laurence E; Sullivan, Brandon M; Retana, Lizett E et al. (2015) IgE-activated basophils regulate eosinophil tissue entry by modulating endothelial function. J Exp Med 212:513-24
Cheng, Laurence E; Locksley, Richard M (2014) Allergic inflammation--innately homeostatic. Cold Spring Harb Perspect Biol 7:a016352
Molofsky, Ari B; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535-49
Cheng, Laurence E; Hartmann, Karin; Roers, Axel et al. (2013) Perivascular mast cells dynamically probe cutaneous blood vessels to capture immunoglobulin E. Immunity 38:166-75