肺动脉高压是肺血管功能和结构改变，导致以肺动脉压力和阻力升高为特征的疾病，最终导致右心衰竭甚至死亡。肺动脉高压是一种高度致死性疾病，但具体分子病理机制尚不清楚，尚无有效治疗手段。我们2004年在Nature报道了一个新血管生长因子AGGF1。 最近我们发现AGGF1在肺动脉高压中起关键作用。AGGF1敲除小鼠肺动脉平均压对比野生型小鼠显著升高，并且伴有其它肺动脉高压表征。我们拟利用AGGF1血管内皮细胞和平滑肌细胞条件性敲除小鼠进一步确认AGGF1在肺动脉高压中的关键作用、阐明AGGF1调控肺动脉高压的信号通路、用AGGF1蛋白靶向治疗肺动脉高压小鼠，并在肺动脉高压病人中筛查AGGF1的突变及罕见变异。本项目的成功完成将确立AGGF1基因为一新的肺动脉高压分子决定因子，阐明AGGF1调控肺动脉血管重构、舒张、肺动脉高压新分子机制，确定AGGF1靶向治疗为一种新的有效的肺动脉高压治疗手段。

Pulmonary artery disease (PAH) is a deadly disease characterized by an increased mean pulmonary artery pressure (mPAP) of >25 mmHg and increased pulmonary vascular resistance due to vascular remodeling, leading to right ventricular failure and death. The underlying molecular pathogenic mechanisms are poorly understood. The current treatments are inefficient to improve the survival of patients and reverse the disease. The long-term objective of this project is thus to identify novel genetic determinants and new molecular mechanisms for PAH and to develop new effective treatments. In 2004, we reported in Nature about the identification of a novel angiogenic factor AGGF1. Recently, we have found that AGGF1 plays a critical role in the pathogenesis of PAH. Homozygous AGGF1 knockout mice are embryonic ally lethal, whereas heterozygous AGGF1 knockout mice spontaneously developed PAH with all relevant features of human PAH patients, including a significantly increased mPAP (27.3 mmHg vs. 16.4　mmHg，P=0.007，n=8), higher total pulmonary resistance, increased muscularization, increased medial wall thickness of pulmonary arteries and right ventricular hypertrophy. However, the molecular mechanisms and signal transduction pathways by which AGGF1 haploinsufficiency causes PAH is unknown. In this project, we plan to utilize AGGF1 knockout mice, endothelial cell-specific AGGF1 knockout mice, and vascular smooth muscle cell-specific knockout mice to conclusively demonstrate the critical role of AGGF1 in the pathogenesis of PAH, to define the molecular mechanisms and signal transduction pathways by which AGGF1 knockout causes PAH, to determine the effects of AGGF1 protein therapy on PAH in a hypoxia-induced mouse model, to identify mutations and rare genomic variants associated with PAH and to determine the association between AGGF expression levels and the pathogenesis of PAH. Successful accomplishment of these goals should lead to identification of a new gene causing PAH (AGGF1), identification of novel molecular mechanisms and previously unrecognized signaling pathways for PAH, and establishment of AGGF1 protein therapy as a new treatment strategy for PAH. This study may also lead to more effective screening and early treatment of high-risk individuals and suggest novel molecular targets for treatment, prevention, and drug development for PAH.