视网膜前列腺素F2α-FP受体信号通路下调导致近视

Myopia is a serious public health issue whose underlying pathogenic mechanisms require additional clarification. This void in our understanding of a cause and effect relationship of this disease is being addressed to identify novel therapeutic approaches that improve its management. It is evident dysfunctional responses by the retina to the visual environment plays a key role in myopia; however, the identity of these changes requires further clarification. To address this question, we used metabolomics to determine for the first time that retinal arachidonic acid (ARA) biosynthesis is downregulated in form deprived guinea pigs. Furthermore, prostaglandin F2α(PGF), a derivative of ARA, also decreased in myopic retinas, and a PGF receptor (FP) agonist inhibited form deprivation myopia development in guinea pigs. These results prompt us to hypothesize that downregulation of the retinal PGF-FP signaling pathway contributes to myopia. To test this hypothesis, we will use a mouse model of this disease since performing detailed cell and molecular experiments in guinea pigs are severely hindered by the lack of appropriate molecular tools such as antibodies. Our specific aims include: (1) determining if the PGF-FP signaling pathway has a regulatory role by evaluating effects of upregulating and downregulating its activity on myopia; (2) identifying specific retinal cell types in which GFP-FP pathway downregulation hastens myopia onset. Study of this project will demonstrate retinal part of myopia pathogenesis, and may propose prostaglandin analogs for myopia treatment.

近视是我国严重的公共卫生问题，发生机制未明，尚无有效的病因学防治手段。视网膜对视觉环境的响应是其中的重要环节，但视网膜中哪些改变导致近视发生尚无定论。我们前期代谢组学研究首次发现近视视网膜中花生四烯酸水平降低，进一步发现其衍生物前列腺素F2α（PGF）水平也下降，而PGF类似物抑制豚鼠近视进展。据此提出假设：视网膜PGF-FP受体信号通路下调导致近视发生。为验证该假设并探讨其机制，我们将 (1)特异性上调和下调视网膜内该信号通路并观察相应的近视发生发展变化，明确该信号通路下调与近视的因果关系；(2)明确视网膜哪些细胞通过PGF-FP信号通路调控近视发生发展，阐明近视发生的细胞和分子机制。本项目将明确近视发生的视网膜环节，为进一步阐明近视发生机理奠定基础。同时，PGF类似物是降眼压的常用药物，这将为“老药新用”治疗近视提供理论依据，推进近视的药物干预研究。

近视是我国严重的公共卫生问题，发生机制未明，尚无有效的病因学防治手段。我们前期代谢组学研究首次发现近视视网膜中花生四烯酸水平降低，进一步发现其衍生物前列腺素F2α（PGF）水平也下降，而PGF类似物抑制豚鼠近视进展。据此提出假设：视网膜PGF-FP受体信号通路下调导致近视发生。为验证该假设并探讨其机制，我们引进了FP受体敲除小鼠，发现敲除小鼠（FP-/-）在4 周、6 周、8 周、10 周时，与野生型同窝仔（FP+/+）相比其屈光、眼轴等生物学参数差异均无统计学意义，说明FP受体敲除不影响小鼠的正常屈光发育；而形觉剥夺2周后， FP-/-与FP+/+相比近视程度相近，说明FP受体敲除不影响小鼠的形觉剥夺性近视进展。.眼底的新生血管性疾病已经成为全球致盲的主要原因之一。最新研究表明，COX-2（PGE2和PGF2α的合成酶）具有促进视网膜血管发育和病理性血管生成的作用，而PGF2α已被证明参与女性生殖系统及多种类型肿瘤中的血管生成过程，因此推测COX-2通过诱导合成前列腺素F2α调控视网膜新生血管的生成。本课题利用FP受体敲除小鼠（FP-/-）及其同窝仔野生型小鼠（FP+/+）构建氧诱导的视网膜病变模型（OIR），发现1)敲除PTGFR可以抑制在高氧及相对低氧环境下的新生血管生成；2) 敲除 PTGFR增加视网膜细胞的凋亡从而抑制新生血管生成；3) PTGFR通过调控CAMKⅡ对血管的生成产生影响。敲除PTGFR可引起视网膜细胞凋亡、抑制生理和病理性血管生成，表明PTGFR可促进血管发育和病理性血管新生，这一作用可能由CAMKII通路介导。PTGFR敲除与COX-2抑制剂作用一致，提示COX-2可能通过PGF2α-PTGFR信号通路调控视网膜血管生成。