血管内皮细胞炎症反应对血管重构起重要作用。既往，我们首次克隆出一个重要炎性信号接头分子AIP1，通过多种血管疾病模型研究证实AIP1缺失能明显加速血管重构的发生发展。新近，我们发现内皮细胞中AIP1存在两种异构体AIP1A、AIP1B。AIP1A在正常生理状态内皮细胞中高表达，能抑制炎症反应；相反，AIP1B在炎性环境下表达明显上调， 且表现为AIP1A相反的作用。但在慢性炎症状态下，由抑制炎性反应的AIP1A向促进炎性反应的AIP1B转换的调控机制及其在内皮细胞激活、血管重构及心血管疾病发生中作用尚未阐明。为此，本项目以AIP1异构体转换为切入点，从异构体转换表达调控—介导信号通路—细胞表型—疾病模型—临床验证这一主线，深入系统地探讨AIP1异构体1A-1B转换调控血管稳态及重构的分子机制。本项目不仅进一步完善血管重构的相关机制，而且为防治血管重构相关疾病提供新的靶点和思路。

Vascular homeostasis is maintained by critical momeostasis factors which exhibit anti-adhesion, anti-coagulation, anti-infection, anti-inflammation, anti-oxidant and anti-aging in the vasculature. The cell type that normally maintains vascular homeostastasis is the vascular endothelial cell (EC). Proinflammatory cytokines and reactive oxygen species, representing common mechanisms for cardiovascular risk factors, induce EC dysunction and vascular remodeling. We have previously identified a potent homeostastais molecule AIP1A (ASK1-interacting protein-1) that is highly expressed in vascular endothelium and suppresses inflammatory, oxidant and apoptotis signaling. Therefore, genetic deletion of AIP1A augments inflammation and cardiovascular diseases in a variety of animal models. We have recently discovered a different AIP1 isoform (AIP1B) that exhibits opposite functions as AIP1A in the vasculature. Moreover, in response to inflamamtion AIP1A is proteolytically degraded wheras AIP1B is transcriptionally upregulated. We hypothesize that a shift from the anti-inflammatory AIP1A to the pro-inflammatory AIP1B during chronic inflammation plays a key role in endothelial activation and inflammatory vascular diseases. Interestingly, human genome-wide association study (GWAS) has identified AIP1 (DAB2IP) gene variants conferring susceptibility to cardiovascular diseases (CAD), and whether these variants promote the shift from AIP1A to AIP1B is unknown. We propose the following specific aims and studies: 1) To define the mechanism by which AIP1 isoforms are regulated in endothelium. We will determine how the novel ubiquitin E3 ligase complex mediates cytokine-induced degradation of AIP1A, and how the histone H3K9 methylation complex epigenetically suppresses AIP1B transcription in resting EC while releases it under inflammation, and if and how the human variants alter AIP1 isoform patterns; 2) To define the mechanisms by which AIP1B enhances EC activation and inflammatory responses. We will determine how AIP1B activates mitochondrial ASK1, mitochondrial dysfunction and ROS production, and if these changes contribute to AIP1B-mediated endothelial activation and immunogenicity associated with CAD; 3) To determine the function of AIP1B isoform in inflammatory cardiovascular disease models. Using both endothelial-specific AIP1B transgenic mice and CRISPR/Cas9-mediated AIP1B-specific knockout mice, we will determine the role of AIP1B in progression of CAD in several mouse models including neointimal formation, graft arteriosclerosis and atherosclerosis ; 4) To correlate AIP1B expression and signaling with cardiovascular diseases and atherosclerotic development using clinical samples. Collectively, these studies should establish the functions of AIP1 isoforms in inflammatory events, and facilitate development of new therapeutic approaches to control chronic inflammation and cardiovascular diseases.