# Exchange Protein directly Activated by cAMP (EPAC): Structure, Function and Therapeutics

> **NIH NIH R35** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $428,510

## Abstract

PROJECT SUMMARY
This is an R35 application in response to RFA-GM-17-002 “Maximizing Investigators’ Research Award (R35)".
Our laboratory focuses on studying the pleiotropic second messenger cyclic AMP (cAMP) system. cAMP is a
major stress signal that regulates a myriad of important biological processes under both physiological and
pathological conditions, including cancer, chronic pain, diabetes, heart failure, and infections. Hence, not
surprisingly, the cAMP signaling cascade is one of the most targeted pathways by current pharmaceuticals. In
multi-cellular eukaryotic organisms, the effects of cAMP are mainly transduced by two ubiquitously-expressed
intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and
the more recently discovered exchange proteins directly activated by cAMP/cAMP-regulated guanine
nucleotide exchange factor (EPAC/cAMP-GEF). While accumulating evidence implicates EPAC proteins as
important stress response switches in the development of various human diseases, major gaps in our basic
understanding of EPAC structures and functions persist. To bridge these gaps, we will apply structural,
pharmacological and genetic approaches to interrogate the mechanisms of action and biological functions of
this important family of signaling molecules, leading to the assessment of EPAC proteins as potential
therapeutic targets in various disease models. The proposed research is based on more than seventeen years of
extensive fundamental studies of EPAC-mediated signaling and directly builds on a several recent
developments in our laboratory, which include the characterization of EPAC knockout mice and the discovery
of first-in-class EPAC specific inhibitors. The combination of complementary structural approaches, novel
genetic animal models and pharmacological probes will enable us to reveal much desired mechanistic insight
and in vivo functions of EPAC proteins. This research plan will also aid in the advancement of new
pharmacological tools for deciphering EPAC-mediated cell signaling and disease mechanisms, which can pave
the way for novel, mechanism-based therapeutic strategies specifically targeting cAMP/EPAC signaling.

## Key facts

- **NIH application ID:** 10198941
- **Project number:** 5R35GM122536-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** XIAODONG CHENG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $428,510
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198941

## Citation

> US National Institutes of Health, RePORTER application 10198941, Exchange Protein directly Activated by cAMP (EPAC): Structure, Function and Therapeutics (5R35GM122536-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198941. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*