Document text
Principal Investigator: Vijay Rathinam
Organization: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
Fiscal Year: 2024
Award: $410,000
Funding agency: National Institute of Allergy and Infectious Diseases
Inflammasome related caspases such as caspase-1, caspase-4, and caspase-11 are a subset of
the caspase family specialized in executing a lytic form of cell death and IL-1 cytokine-based
inflammatory response. The activation of these inflammatory caspases is strongly coupled to
innate immune detection of infections and cellular perturbations via canonical and noncanonical
inflammasomes. Inflammasomes are multiprotein complexes in the cytosol assembled in
response to wide variety of pathogen-associated molecular patterns (PAMPs) including nucleic
acids, toxins, flagellin, and cell wall components and endogenous danger signals (danger-
associated molecular patterns, or DAMPs) such as ATP and uric acid crystals. The assembly of
inflammasome complex leads to the autoproteolytic activation of inflammatory caspases.
Enzymatically active versions of inflammatory caspases activate a pore forming protein called
gasdermin D, which lyses the cells via plasma membrane perforation. Active caspase-1 also
cleaves the inflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms. Inflammatory
caspases are important for initiating the inflammatory response against a wide variety of
pathogens including bacteria and viruses. Inflammatory caspases also play crucial roles in sepsis,
a major life-threatening condition associated with infections. Extracellular vesicles (EVs) are
membrane-bound structures abundantly released by our living cells into the extracellular space.
EVs are packaged with proteins, lipids, and RNAs, and EVs have emerged as a crucial mode of
inter-cellular transfer of all three cargoes. EV-cargoes are functional and modulate the physiology
of the recipient cells. However, the role of EVs in the inflammasome signaling is poorly
understood. This proposal seeks to comprehensively address this critical knowledge gap in three
specific aims. Aim 1 will characterize the impact of host-derived EVs on inflammatory caspase
activation by PAMPs. Aims 2 and 3 will demonstrate the molecular and cellular mechanisms by
which the host-derived EVs regulate PAMP-activation of inflammatory caspases. In summary, this
proposal will reveal a new role for host-derived EVs in inflammasome responses in the context of
host defense with great implications for human infectious diseases and sepsis.
Terms: <Address><Albumins><Amphoterin><Amphoterin Gene><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Apoptosis-Related Cysteine Protease Caspase 1><Bacteria><Bacterial Infections><Beta Proprotein Interleukin 1><Binding><Biochemical><Blood><Blood Reticuloendothelial System><CASP-1><CASP1><CASP1 gene><CD14><CD14 gene><CD47><CD47 Antigen><CD47 Glycoprotein><CD47 gene><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Caspase><Caspase Gene><Caspase-1><Caspase-1 Gene><Cell Body><Cell Communication and Signaling><Cell Death><Cell Fractionation><Cell Signaling><Cell Wall><Cell membrane><Cell surface><Cell-Death Protease><Cells><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Chronic><Circulation><Communicable Diseases><Complement><Complement Proteins><Complex><Confocal Microscopy><Coupled><Cre-Lox><Cre-LoxP><Cre/LoxP><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Cytolysis><Cytoplasmic Membrane><Cytosol><Detection><Development><Disease><Disorder><Distant><Drugs><Electrons><Endosomes><Endothelial Cells><Event><Extracellular Space><FM1 Gene Product><Family><Flagellin><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Transcription><Genetic Transcription><Germ Lines><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Homolog of Drosophila TOLL><Host Defense><Host Factor><Host Factor Protein><Human><ICE Protease><ICE-like protease><IFN-Gamma-Inducing Factor Gene><IFN-gamma-Inducing Factor><IGIF><IGIF Gene><IL-1><IL-1 Gamma><IL-1 Gamma Gene><IL-1 beta><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1 β><IL-1-b><IL-18><IL-18 Gene><IL-1BC><IL-1b Converting Enzyme><IL-1g><IL-1g Gene><IL-1β><IL1><IL1-Beta><IL1-β><IL18><IL18 Protein><IL18 gene><IL1B Protein><IL1B-Convertase><IL1BC><IL1BCE><IL1F2><IL1F4><IL1F4 Gene><IL1β><Image><Immune><Immune Surveillance><Immune response><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunomodulation><Immunosurveillance><In Situ><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Innate Immune System><Integration Host Factors><Integrin-Associated Protein><Intercellular Space><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin 1beta><Interleukin I><Interleukin-1><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-1 beta><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Interleukin-1β><Intestinal Leakage><Intracellular Communication and Signaling><Knowledge><LPS-binding protein><Leaky Gut><Life><Lipids><Literature><Location><Lymphocyte-Stimulating Hormone><Lysis><Lytic><MER6><MGC12320><MGC12320 Gene><Macromolecular Protein Complexes><Macrophage Cell Factor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Medication><Membrane><Methods><Mice><Mice Mammals><Microscopic><Miscellaneous Antibiotic><Modern Man><Molecular><Molecular Interaction><Multiprotein Complexes><Murine><Mus><Mutant Strains Mice><Myeloid Cells><Negative Beta Particle><Negatrons><Non-Polyadenylated RNA><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Nucleic Acids><Outcome><Pathway interactions><Pattern><Pattern recognition receptor><Perforation><Pharmaceutical Preparations><Physiology><Plasma Membrane><Play><Preinterleukin 1 Beta><Proteins><RNA><RNA Expression><RNA Gene Products><Receptosomes><Regulation><Ribonucleic Acid><Role><SBP-1><SBP-1 Gene><Sepsis><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Surface Antigen Identified by Monoclonal Antibody 1D8><T Helper Factor><TLR4><TLR4 gene><Toll Homologue><Toxin><Transcription><Translational Activation><Trioxopurine><Uric Acid><VDAC1><VDAC1 gene><Vesicle><Virus><Work><bacteria infection><bacterial disease><biological signal transduction><blood infection><bloodstream infection><cell type><clustered regularly interspaced short palindromic repeats screen><complementation><cystein protease><cystein proteinase><cysteine endopeptidase><cytokine><defined contribution><developmental><drug/agent><extracellular vesicles><flow cytophotometry><host response><imaging><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><insight><lipopolysaccharide-binding protein><lymphocyte activating factor><membrane structure><microbial products><mouse mutant><necrocytosis><pathogen><pathway><plasmalemma><pore forming protein><porin><response><social role><subcellular fractionation><toll-like receptor 4><virtual>