R01AI165866

Exploiting and Enhancing IgE-Binding Epitopes of the 2S Albumins of Peanuts and Tree Nuts - Abstract:

IgE-mediated food allergy to peanuts (PN) and/or tree nuts (TN) is a major health problem in the United States, affecting approximately 4% of children and up to 2% of adults. Co-allergy among these foods is relatively common and is difficult to identify given the more common finding of co-sensitization. Recent progress with early administration of these foods and oral immunotherapy, especially in conjunction with anti-IgE, have shown promise. Unfortunately, these approaches are not successful for all patients and, even when successful, have limitations regarding compliance and unpredictable breakthrough.

There are significant, unmet needs in this field, including the need to: 1) understand the immunologic details of IgE-mediated activation of mast cells by allergens from PN and TN, 2) understand the molecular basis for co-allergy among TN and between PN and TN, 3) develop improved diagnostics to identify clinically relevant peanut and tree nut allergy, and 4) design new approaches to interfere with allergic reactions caused by peanuts.

The overarching concept of this proposal is that the 2S albumins are the most important allergens of peanuts and tree nuts and are the key to understanding PN and TN allergy and cross-reactivity, as well as developing potent diagnostic and potentially therapeutic reagents. Preliminary data show that we have: 1) developed a sensitive ELISA assay, 2) identified the critical amino acids within IgE-binding peptides, 3) demonstrated that conformationally constrained (3D) peptides bind IgE strongly, and 4) shown that patients with PN allergy alone and PN + TN allergy identify different patterns of peptides in a microarray assay.

We hypothesize that: 1) we can optimize IgE binding to existing peptides and discover novel peptides with enhanced binding, 2) there are cross-reacting epitopes of PN and selected TN, and 3) IgE binding to existing and novel peptides will have potential predictive value for important clinical outcomes.

To achieve these goals, we propose to: 1) perform positional amino acid (AA) screening to optimize binding of IgE to peptides, 2) utilize click chemistry and stapling technology to enhance IgE binding and resistance to proteases, and 3) use microarray technology to assess IgE binding with well-defined samples from patients with PN, WN, PECN, CN, and PISN allergy, as well as from those undergoing clinical trials.

Success in this project will establish a new intellectual framework regarding allergen/IgE interactions, describe, at least in part, the molecular basis for these co-allergies, design new diagnostics, and move us along the path toward development of an oral, peptide-based treatment for peanut allergy.

The Regents Of The University Of Colorado

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Aurora, Colorado 800452507 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)

Amendment Since initial award the End Date has been extended from 08/31/26 to 08/31/31 and the total obligations have increased 422% from $801,160 to $4,183,113.