R01AI168240

3-Dimensional Genomic Architecture in Innate Lymphoid Cells and Allergic Inflammation - Project Summary

Group 1, 2, and 3 innate lymphoid cells (ILC1, ILC2, and ILC3) are immune effector cells that contribute to tissue homeostasis and host defense against nearly all classes of pathogens. However, their dysregulation also plays key roles in prevalent diseases such as cancer, obesity, asthma, and colitis. The transcription factor (TF) networks that control the development and functions of the different groups of ILC have recently been identified. Yet, how the chromatin accessibility landscape and the 3-dimensional (3D) genome architecture determine the development, homeostasis, and effector functions of ILC is largely unknown.

Thus, the overarching goal of this proposal is to uncover how the 3D genomic and epigenetic architecture regulate the development of each ILC subset and their contribution to the development of allergic airway inflammation. It is now well-established that the transcriptional repressor ID2 determines the commitment and identity of the ILC lineage. As such, ID2 expression is now considered a hallmark of all ILC subsets in mice and humans.

Our preliminary data indicates that ID2 expression is controlled in ILC1, but not ILC2 or ILC3, by specific long-range DNA interacting loops between specific distal cis-regulatory elements (CIS-RE) and the ID2 promoter. Moreover, we showed that ablation of these promoter-CIS-RE interactions in mice leads to a dramatic reduction in ILC1 in multiple tissues, while the development and functions of ILC2 and ILC3 were unaltered. Thus, our findings indicate for the first time that ID2 expression is regulated by long-range DNA interacting loops between the ID2 promoter and distal CIS-RE in an ILC-subset specific manner. Moreover, it indicates that ablating these CIS-RE is a powerful strategy to generate genetic tools to study the roles of each ILC subset in the context of an otherwise intact immune system.

Yet, how the chromatin accessibility landscape and the 3D genomic architecture determine ID2 expression specifically in ILC2 and ILC3 remains unknown. Thus, in aims 1 and 2 of this project, we will use novel genetic tools that we generated, single cell sequencing technologies, and HIC to elucidate how chromatin folding and accessibility determine the development and functions of ILC2 and ILC3 through the regulation of ID2 expression. In aim 3, we will exploit the specificity of these regulatory mechanisms to study the functions of ILC2 during allergic airway inflammation in the context of an otherwise intact immune system.

Collectively, these studies will answer the long-standing question of how ID2 expression is controlled to drive the ILC fate. Moreover, it will generate an atlas of the 3D genomic landscape of each ILC subset, which will allow us to identify unknown non-coding regulatory regions that are critical for the function and development of ILC1, ILC2, and ILC3. Importantly, through the identification of specific regulatory mechanisms in each ILC subset, we have created novel mouse genetic tools to study the functions of each group of ILC in the context of an otherwise intact immune system. This might unveil novel therapeutic approaches to target ILC during inflammatory disorders.

Trustees Of The University Of Pennsylvania

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]

Pennsylvania United States

State-Wide

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

Amendment Since initial award the End Date has been shortened from 05/31/27 to 05/31/25 and the total obligations have increased 400% from $645,276 to $3,226,380.