早产儿视网膜病变(ROP)以视网膜血管病理增生为特征，是儿童致盲的主要原因。临床显示：早产儿接受腺苷受体非特异拮抗剂咖啡因治疗呼吸暂停随访视网膜血管病变减弱，我们研究发现：咖啡因治疗或腺苷A2A受体失活减轻氧诱导视网膜病变(OIR)，不影响正常血管发育。我们提出异常A2A受体信号为抑制视网膜病理性血管生成而不干扰血管正常发育的新靶点。本研究利用星形胶质、巨噬细胞，视网膜神经元等细胞特异A2A受体敲除和小鼠OIR/大鼠50-10%氧模型，阐明：1.咖啡因和A2A受体拮抗剂KW6002抑制视网膜病理血管增生不影响正常血管发育的细胞和分子机制；2.咖啡因和KW6002对OIR保护作用有效时间窗及高氧和低氧阶段的细胞机制；3.通过KW6002和咖啡因/抗VEGF联用，阐明A2A受体信号和非A2A受体信号协同调控ROP的分子基础。结合咖啡因临床安全性，确立异常A2A受体信号新干预靶点有转化医学前景。

Retinopathy of prematurity (ROP) is caused by oxygen-induced damage to developing retinal vasculatures and has become a major cause of childhood blindness in many parts of the world. Inspired by the clinical observation of the reduced severity of ROP in premature infants after caffeine treatment for sleep apnea, we recently made a novel discovery that genetic and pharmacological inactivation of the adenosine A2A receptor (A2AR) (by non-selective adenosine antagonist caffeine or A2AR antagonist KW6002) attenuated oxygen-induced retinopathy (OIR) without affecting normal development of retinal vascularization. Based on these findings, we proposed that abnormal retinal A2AR signaling may be selectively targeted for treating ROP without server unwanted effect on normal retinal development. Equipped with a series of cell-type specific A2AR knockout models with selective deletion of A2ARs in bone marrow, astrocytes, macrophages and retinal neurons and coupled with mouse OIR model and rat 50/10 oxygen oscillation model of ROP, we will first establish the critical role of the A2AR signaling in bone marrow cells, astrocytes, microglial cells and retinal neurons as well as the molecular signaling pathway (cAMP-CXCR4/SDF-1 and cAMP-Csk-IFN-γ) in differentially controlling normal developmental retinal vasculatures and oxygen-induced pathological angiogenesis and retinopathy. Then, we will identify the effective therapeutic window (i.e. hyperoxic or hypoxic phases) as well as their cellular bases (retinal neuronal apoptosis and astrocytic function) for caffeine and KW6002 to confer protection against OIR. Lastly, we will critically evaluate combined caffeine-KW6002 and KW6002-anti-VEGF treatment to identify therapeutic strategies with maximal synergistic effect on ROP pathological with minimal effect on physiological development of retinal vasculatures. The information derived from this study will not only elucidate the cellular and molecular mechanism underlying selective control pathological angiogenesis by targeting abnormal A2AR signaling, but also provide the proof-of-principle evidence to translate the novel caffeine- and A2AR antagonist-based therapies for prevention and treatment of ROP.