巩膜PPARα调控胶原合成及其在近视形成中的作用

Myopia is a common refractive error caused by a mismatch between optical power and ocular axial length. As its pathogenesis is poorly understood, there are no effective means for treating this sight threatening condition. A decline in scleral collagen biosynthesis along with extracellular matrix remodeling are key events underlying myopia formation. However, the regulatory mechanisms underlying these changes are not yet clear. In our previous study, transcriptomics of form deprivation myopia was analyzed in mice. We found treatment with a PPARα agonist for 2 days and 4 weeks during form deprivation suppressed myopia development in wildtype mice. On the other hand, in PPARα knockout mice scleral collagen synthesis declined more and myopia was more severe than that in the wildtype PPARα agonist treated mice.These results, form the basis for this proposal whose underlying hypothesis is that scleral PPARα activity contributes to the regulation of scleral collagen biosynthesis. Increases in its activity suppresses extension of the ocular axis by increasing extracellular matrix rigidity and in turn myopia formation. We anticipate that by proving the correctness of this hypothesis we will demonstrate that PPARα activity modulation contributes to myopia progression. This research will help decide if drug-induced PPARα stimulation is a potential approach for reducing myopia progression in a patient population.

近视是常见的屈光不正，其发病机制仍未明了，也无有效的病因学防治手段。巩膜胶原合成减少是近视形成的关键环节之一，但胶原合成的调控机制尚未明了。我们前期发现小鼠形觉剥夺近视巩膜转录组，发现剥夺2天、4周后巩膜PPARα信号通路被富集及功能下调，而PPARα激动剂可抑制形觉剥夺近视形成，小鼠PPARα敲除后出现明显的近视及巩膜胶原减少。基于以上结果，提出本项目的科学假设：巩膜PPARα通过调控巩膜胶原合成，从而导致眼轴延长及近视形成。本项目将首先进一步证实巩膜PPARα参与近视的形成；然后，再明确巩膜PPARα可调控巩膜胶原合成；最后，探讨PPARα调控胶原合成的机制。通过上述研究，有望明确巩膜PPARα在屈光发育和近视形成中的作用及机制，阐明巩膜胶原合成及细胞外基质重塑的调控方式，从而进一步阐明近视发生发展的机制，为近视的药物干预提供新的依据。

近视是常见的屈光不正，其发病机制仍未明了，也无有效的病因学防治手段。巩膜胶原合成减少是近视形成的关键环节之一，但胶原合成的调控机制尚未明了。本项目通过小鼠形觉剥夺近视巩膜转录组，发现巩膜PPARα信号通路被富集及功能下调。而全身PPARα敲除小鼠和巩膜PPARα特异性敲除小鼠均出现近视，而视网膜PPARα特异性敲除小鼠并不影响屈光，小鼠PPARα敲除后巩膜胶原减少。同样，PPARα激动剂和巩膜过表达PPARα可抑制形觉剥夺近视形成的形成。PPARα 的激动剂抑制豚鼠形觉剥夺近视的发展，而拮抗剂促进正常豚鼠向近视方向发展。以及，PPARγ的激动剂和拮抗剂对近视的影响与PPARα对豚鼠近视有异曲同工之处。体外实验证明，PPARα激动剂GW7647对人巩膜成纤维细胞胶原的无影响。说明在正常情况下，PPARα激动剂GW7647对巩膜上胶原无影响，这与豚鼠体内药物注射实验一致。同时，研究发现PPARα通路和前列腺素E2受体（EP2）通路相互交联可调节豚鼠近视发展过程的低氧信号通路的传到。而缺氧诱导因子（HIF-1α）在近视过程中上调是本课题组近期发现在近视上提供新思路。同时我们发现了小鼠近视过程存在巩膜内缺氧通路和eIF2α通路的激活。基于以上结果，我们能够证明本项目的科学假设：巩膜PPARα通过调控巩膜胶原合成，从而导致近视形成。提出近视诱导过程中，巩膜缺氧可抑制ppara信号通路，从而参与胶原合成调控导致近视形成。研究不仅进一步明确了近视发生的机制，也为近视的药物干预提供新的依据。