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

cAMP 直接激活的交换蛋白 (EPAC)：结构、功能和治疗

基本信息

批准号：
10198941
负责人：
XIAODONG CHENG
金额：
$ 42.85万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

项目摘要

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.

项目概要这是响应 RFA-GM-17-002“最大化研究者研究奖 (R35)”的 R35 申请。我们实验室重点研究多效性第二信使环磷酸腺苷（cAMP）系统。主要应激信号，在生理和心理条件下调节无数重要的生物过程病理状况，包括癌症、慢性疼痛、糖尿病、心力衰竭和感染。令人惊讶的是，cAMP 信号级联是当前药物最具针对性的途径之一。在多细胞真核生物中，cAMP 的作用主要由两种普遍表达的转导细胞内 cAMP 受体，经典蛋白激酶 A/cAMP 依赖性蛋白激酶 (PKA/cAPK) 和最近发现的由 cAMP/cAMP 调节的鸟嘌呤直接激活的交换蛋白越来越多的证据表明 EPAC 蛋白是核苷酸交换因子 (EPAC/cAMP-GEF)。各种人类疾病发展过程中重要的应激反应开关，我们的基本知识的主要差距为了弥合这些差距，我们将应用结构性、药理学和遗传学方法来探究其作用机制和生物功能这一重要的信号分子家族，导致 EPAC 蛋白的潜力得到评估所提出的研究基于十七年多的研究。对 EPAC 介导的信号传导进行了广泛的基础研究，并直接建立在最近的几个研究基础上我们实验室的进展，包括 EPAC 基因敲除小鼠的表征和发现一流的 EPAC 特异性抑制剂互补结构方法的组合，新颖。遗传动物模型和药理学探针将使我们能够揭示许多想要的机制见解该研究计划也将有助于新的进展。破译 EPAC 介导的细胞信号传导和疾病机制的药理学工具，可以为专门针对 cAMP/EPAC 信号传导的新型基于机制的治疗策略。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis.

DOI：
10.3390/cells10102750
发表时间：
2021-10-14
期刊：
Cells
影响因子：
6
作者：
Ni Z;Cheng X
通讯作者：
Cheng X

Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development.

DOI：
10.1161/atvbaha.119.314238
发表时间：
2020-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Robichaux WG 3rd;Mei FC;Yang W;Wang H;Sun H;Zhou Z;Milewicz DM;Teng BB;Cheng X
通讯作者：
Cheng X

Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes.

区室化的环核苷酸对心肌细胞中肥大性磷脂酶 Cγ 信号传导的调节具有相反的作用。