# Shedding new light on cytokine signaling through molecular engineering

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2022 · $384,999

## Abstract

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.

## Key facts

- **NIH application ID:** 10501747
- **Project number:** 1R35GM147179-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Juan Luis Mendoza
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $384,999
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501747

## Citation

> US National Institutes of Health, RePORTER application 10501747, Shedding new light on cytokine signaling through molecular engineering (1R35GM147179-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10501747. Licensed CC0.

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