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 Univ. Of Colorado

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

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

Aurora, Colorado 800452560 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 321% from $801,160 to $3,375,729.