R01AI156268

Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation - Project Summary

The innate immune system is the first line of defense against invading pathogens and intimately collaborates with the adaptive immune system to maintain physiological homeostasis. However, components of the immune response can sometimes become dysfunctional, failing in this protective role and even directly causing a variety of autoimmune diseases.

Immune dysfunction arises from an interplay of genetic and environmental factors; however, a mechanistic understanding of the various proteins and pathways that drive these conditions remains incomplete. In particular, it is known that immune sensors, which are typically dedicated to protection against infection, are sometimes usurped and instead initiate and propagate autoimmune diseases such as systemic lupus erythematosus (SLE) and Crohn's disease.

Specifically, self-induced signaling by nucleic acid-sensing endosomal Toll-like receptors (TLRs 7 and 9) and the unchecked production of pro-inflammatory cytokines (e.g., type I interferons; IFN-I) in plasmacytoid dendritic cells (PDCs) are key events in the pathogenesis of numerous autoimmune conditions. Thus, compounds that can suppress the production of these cytokines in PDCs would be clinically useful agents for the treatment of such diseases.

Recently, loss-of-function studies of the poorly characterized endolysosomal solute carrier gene family 15 member 4 (SLC15A4) in lupus mouse models revealed significantly reduced disease manifestation as well as near complete suppression of TLR7/9-mediated production of IFN-I and other pro-inflammatory cytokines.

In this application, we have leveraged our lab's innovative chemoproteomic fragment-based ligand discovery platform to develop a suite of chemical probes that engage SLC15A4 in human PDCs, block SLC15A4-mediated transport, and suppress IFN-I production in human and mouse primary PDCs.

We will utilize an interdisciplinary strategy that draws upon the fields of chemical biology, immunology, and mass spectrometry to illuminate how SLC15A4 controls TLR-mediated production of IFN-I in primary human and mouse immune cells and evaluate pharmacological inhibition in vivo.

Specifically, we will investigate the effects of SLC15A4 pharmacological inhibition on endolysosomal homeostasis, on the protein interaction network of SLC15A4, and on signaling in immune cells crucial to autoimmune pathophysiology. Critically, we will assess the therapeutic potential of SLC15A4 in disease models of inflammation, such as lupus.

The chemical tools generated and knowledge gained from these studies are certain to greatly advance our understanding of SLC15A4 biology, enabling the identification of novel strategies to treat human autoimmune diseases.

Scripps Research Institute

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]

La Jolla, California 920371000 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 468% from $584,460 to $3,319,604.