R01AI153422

Role of Ezrin in Macrophages - Project Summary

Macrophages (MFS) play a crucial role in killing microorganisms, engulfing dead cells and debris, and regulating the immune response. They act as gatekeepers of tissue health, including the lungs. The lung-tissue-resident MFS (TR-MFS) consist of interstitial and alveolar MFS, each with complementary but distinct functions.

In response to infections, the lungs are rapidly populated by waves of LY6C+ circulating monocytes. These monocytes, along with TR-MFS, fight the infection and facilitate the resolution of the inflammatory response. However, many chronic lung inflammatory diseases, such as cystic fibrosis (CF), are associated with dysregulated MF function.

Our long-term goal is to understand how different lung MF populations contribute to lung hyper-inflammation and infection, and to elucidate the biology of these distinct cell populations. The objective of this proposal is to characterize Ezrin's role in monocyte/MF function. We hypothesize that Ezrin controls monocyte/MF cortical actin organization and signal transduction events in response to inflammatory/infectious stimuli. These cellular changes allow the MFS to spread, move, phagocytize, and survive, thus shaping the magnitude and quality of the lung immune response to infections.

The rationale for these studies is that low Ezrin levels have been found in MFS from patients with CF (our work), and other investigators have also reported low Ezrin levels in blood cells from individuals with asthma. By elucidating the molecular mechanism by which Ezrin shapes lung MF functions, we could identify potential therapeutic targets for lung diseases.

Our specific aims will test the following hypotheses: (Aim 1) Ezrin is required for the signaling that drives MFS to adhere to the lung extracellular matrix and to differentiate in response to LPS; (Aim 2) Ezrin is needed for efficient phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa, two microorganisms that CF patients fail to efficiently eradicate from their lungs; (Aim 3) The acquired "cellular Ezrin low-state" inactivated CF MFS is central to their uncontrolled immune signaling and reduced phagocytosis.

The contribution of this research is significant since very little is known about Ezrin's role in regulating lung MF activation. Our proposed research is innovative because we will use an unprecedented mouse model in which Ezrin is knocked out in monocytes and MFS. Thus, the proposed studies will investigate in depth the consequences of Ezrin loss in monocytes and MFS during lung infection and inflammation.

Yale Univ

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]

New Haven, Connecticut 065191612 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 376% from $663,843 to $3,162,244.