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Principal Investigator: Juan Luis Mendoza
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $72,550
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
Cytokine signaling is essential to the initiation of the immune response against microbial infection and cancer.
The immune system is composed of two mechanisms of defense defined as the innate and adaptive immune
systems, both of which critically rely on cytokine signaling to function. The innate immune system acts early
during an infection or cancer and includes the type I IFN response. The adaptive immune system becomes fully
active after approximately seven days. Although this response is delayed relative to the innate system, the time
is needed to mount a T-cell response that is potent and specific. Interleukin-2 and interferon gamma are
examples of cytokines that shape the response of the adaptive immune system. There are dozens of other
cytokine families that each play an important role in the immune system including hematopoiesis, inflammation,
apoptosis as well as many others. Understanding how cytokines signal, the genes they induce, and their
functions are critical to understanding human health and disease. Recent examples of engineered cytokines
demonstrate that tuning of cytokine signaling can drastically alter a cytokine’s response and may offer promising
new therapeutic approaches. In this proposal, we aim to use protein engineering technologies to fill the large
gaps in knowledge of cytokine signaling which may reveal new targets and approaches for therapeutic
intervention.
The paradigm of cytokine signaling is that cytokines drive the dimerization of cytokine receptors. Janus
kinases (JAKs) are believed to be constitutively bound to the cytokine receptors. Upon receptor dimerization, the
JAKs cross phosphorylate each other as well as the receptors. Signal transducers and activators of transcription
(STATs) bind to the phosphorylated receptors, are then phosphorylated, dimerize, and translocate to the nucleus
to elicit gene and functional responses. Recent tool development in our lab provides a streamlined approach to
characterize protein-protein interactions which occur intracellularly, challenge assumptions in the field, and
provide an opportunity to understand how every step in cytokine signaling contributes to cytokine signaling. We
aim to show how altering these interactions tune cytokine signaling and response gene and functional signature.
Terms: <Adaptive Immune System><Apoptosis><Apoptosis Pathway><Area><Binding><Biochemistry><Biological Chemistry><Biophysics><Cancers><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cellular Immune Function><Clinical><Co-Stimulator><Costimulator><Cytokine Receptors><Cytokine Signal Transduction><Cytokine Signaling><Defense Mechanisms><Dimerization><Disease><Disorder><Engineering><Epidermal Thymocyte Activating Factor><Equipment><Family><Genes><Health><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Human><IFN><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-2><IL2 Protein><Immune Interferon><Immune response><Immune system><Immunological response><Infection><Inflammation><Innate Immune System><Interferon Gamma><Interferon Type II><Interferons><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><JAK kinase><Janus kinase><Knowledge><Lymphocyte Mitogenic Factor><Malignant Neoplasms><Malignant Tumor><Mitogenic Factor><Modern Man><Molecular><Molecular Interaction><Nucleus><Phosphorylation><Play><Programmed Cell Death><Protein Dimerization><Protein Engineering><Protein Phosphorylation><Proteins><Receptor Protein><Role><STAT protein><Shapes><Signal Transducer and Activator of Transcription><Signal Transduction><Signal Transduction Systems><Signaling><System><T cell growth factor><T cell response><T-Cell Growth Factor><T-Cell Stimulating Factor><Technology><Therapeutic><Therapeutic Intervention><Thymocyte Stimulating Factor><Time><acquired immune system><adaptive immune response><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><blood cell formation><cytokine><genetic protein engineering><host response><immune function><immune system response><immunoresponse><intervention therapy><lFN-Gamma><malignancy><microbial><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><protein design><protein protein interaction><psychological defense mechanism><receptor><response><social role><tool development>