R01AI167933

Regulation of IGE and Atopic Itch - Project Summary

The current paradigm of allergic inflammation asserts that allergen crosslinking of FCER1-bound to allergen-specific IGE leads to mast cell and basophil degranulation and release of effector molecules like histamine and leukotrienes. AD is a classic allergic disorder like asthma and food allergy and the most common chronic illness of childhood and is often a lifelong disease. However, the specific role of IGE in AD pathogenesis is not well characterized and controversial.

In 2021, the Kim lab showed that IGE-mediated mast cell stimulation triggers histamine-induced itch in the steady state. Intriguingly, under AD-like conditions, IGE triggers basophils to elicit non-histaminergic itch through the mediator leukotriene C4 (LTC4). Patients with AD demonstrated increased IGE reactivity and basophil activation in association with acute itch flares.

In parallel, our studies demonstrated for the first time that IGE glycosylation, and specifically sialic acid, is a determinant of IGE pathogenicity. Increased sialic acid content of IGE resulted in more significantly mast cell degranulation in both murine and human models. Our studies raised the possibility that pathogenicity of IGE can be variably regulated to control cellular responses through alterations in glycosylation.

Taken together with the variations in IGE cellular interactions in steady state and AD-associated itch demonstrated by Dr. Kim's group, our central hypothesis is that unique IGE glycosylation patterns result in enhanced mast cell-mediated itch in the steady state, while also promoting basophil-mediated acute itch flares in AD. We will test our central hypothesis and attain the objective of the application by pursuing the following three specific aims:

1) Do different glycoforms of IGE mediate itch in the steady state?
2) Does AD-associated inflammation result in the production of different glycoforms of IGE?
3) Identify itch-specific IGE glycosylation patterns in human AD.

The role of specific IGE glycosylation in contributing to itch in AD is unknown and regulation of these processes is poorly defined. The work from this proposal will allow us to pursue our long-term goal of establishing how IGE glycosylation and basophils can be targeted to yield innovative treatments for itch and AD.

The overall objective of our proposal is to test the mechanisms by which IGE glycosylation affects mast cell and basophil activation, respectively, contributing to the development of different forms of itch. There is an urgent need to decrypt the role of IGE glycosylation in AD in an effort to yield more effective therapies for AD-associated itch.

These studies will have impact beyond AD to diseases in which IGE and itch are implicated including allergic contact dermatitis, bullous pemphigoid, and chronic spontaneous urticaria among others with shared mast cell and/or basophil pathologies.

The General Hospital Corporation

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]

Boston, Massachusetts 021142621 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 390% from $662,308 to $3,243,540.