巩膜内RXRα受体调控巩膜胶原研究合成及调控近视形成的机制

Myopia is a refractive error that has a high worldwide incidence, but its pathogenesis and treatment are still unclear. Studies have shown that increases in intraocular retinoic acid leads to optic axial extension and myopia, but the underlying mechanisms and modalities as well as positions are not apparent. With our previous use of RNA-sequence technology, we found that RXRα and its regulatory downstream target gene are upregulated in the sclera of form deprived mice. Also we found that RXRα agonists regulate collagen synthesis in human scleral fibroblasts. Therefore, we hypothesized " that retinoic acid (RA) regulates scleral collagen synthesis through binding to RXRα receptor to affect myopia progression." The first step in this projects entails determining the association between changes in RXRα expression and form deprivation with scleral collagen synthesis. recovery mouse retina, sclera RXRα and sclera collagen changes, and using specific knocked down sclera RXRα that study its effect on refractive development and myopia, to clearly describe RXRα involved in the formation of form deprivation myopia and recovery. Secondly, we will study RXRα scleral collagen biosynthesis which participate in the formation. Overall these studies will determine if RXRα is a potential drug target to reduce myopia occurrence and development, and provide a new theoretical basis for the search for possible intervention myopia specific drugs.

近视是发病率高的屈光不正，但其发病机制未明。研究已发现眼内视黄酸含量增加可导致眼轴延长以及近视形成，但其作用部位、机制和方式均未明。我们利用RNA-seq发现形觉剥夺近视巩膜内RXRα及其下游调控的靶基因表达均有增加，RXRα激动剂能够抑制人巩膜成纤维细胞中胶原的合成。因此提出"RA可能通过巩膜RXRα受体调控胶原合成从而调控近视形成"工作假说。本项目将首先通过研究形觉剥夺及恢复小鼠视网膜、巩膜的RXRα以及巩膜胶原的变化，并特异性敲减巩膜RXRα研究其对屈光发育和近视的作用，明确RXRα参与形觉剥夺近视的形成及恢复；其次，研究RXRα调控巩膜胶原的合成的机制；最后进一步筛选和验证与RXRα共同作用的调控因子。通过上述研究，有望阐明RXRα在巩膜细胞外基质重塑中的调控作用及其对近视的影响，从而进一步阐明近视发生发展的机制，为寻找可能的特异性近视干预药物提供新的理论依据。

近视是全球发病率高的屈光不正，但其发病机制未明。本课题提出“RA可能通过巩膜RXRα受体调控胶原合成从而调控近视形成”工作假说。我们前期通过RNA-seq发现形觉剥夺近视巩膜内RXRα及其下游调控的靶基因表达均有增加，RXRα激动剂能够抑制人巩膜成纤维细胞中胶原的合成。因此本项首先明确巩膜RXRα参与形觉剥夺近视的形成，发现小鼠形觉剥夺性近视过程中，巩膜RXRα及巩膜胶原下降。同时，特异性敲减小鼠巩膜RXRα后可诱导近视形成。其次，通过RXRα拮抗剂HX53l下调豚鼠巩膜RXRα及其下游靶基因的表达，干扰RXRα能够抑制人巩膜成纤维细胞1型胶原表达以及RXRα过表达能够促进小鼠巩膜1型胶原的表达,明确巩膜RXRα调控巩膜胶原合成的机制。最后，寻找与RXRα相互作用共同调控胶原的因子，通过特异性巩膜PPARα/RXRα敲减诱导近视形成，特异性巩膜PPARα/RXRα双敲小鼠下调巩膜胶原的调控以及共同激动PPARα/RXRα促进1型胶原的表达，明确RXRα与PPARα相互作用共同调控巩膜细胞外基质胶原的合成进而影响近视的过程。为近视的机制研究提供研究新方向。