Investigating the Roles of the Srebp2-Bmp2 Pathway in Mouse Eye Size Control and Myopia Development

Project: Research

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Description

Human eyeballs get bigger in size as we grow up, from an average axial length of ~16mm at birth to ~24mm at puberty. If an eyeball grows too big or too fast, its size and optic parameters do not match, leading to myopia (near-sightedness). According to the recent surveys, about 25% children aged 6-8 years in Hong Kong are myopic and the percentage increases to about 60% in 12-year-old students, presenting an alarming public health issue. Studying the basic mechanisms of eye size control is important for understanding myopia development and formulating anti-myopia treatments. In our preliminary study, we discovered a novel function of the transcription factorSterol regulatory element binding protein 2 (Srebp2)in mouse eye development.Srebp2functions in the retinal pigment epithelium (RPE) to promote eye growth during the first two postnatal weeks, which is the most rapid ocular size growth period in mice. RNA-Seq analysis identified thatBone morphogenetic protein 2 (Bmp2) is downstream of Srebp2, and we further showed thatSrebp2represses the expression ofBmp2in mouse RPE.In vivofunctional studies demonstrated that theBmp2level in the RPE is inversely correlated with mouse eye size. Adeno-associated virus (AAV)-mediated RPE-specific overexpression ofBmp2leads to smaller eyes, whileBmp2knockdown in the RPE leads to bigger eyes. Together, we showed that BMP2 is an eye growth STOP signal and thatSrebp2controls mouse eye size via its negative regulation ofBmp2in the RPE. This proposal is undertaken to further solidifythe hypothesis that theSrebp2-Bmp2pathway controls eye size during both normal ocular growth and myopia development.Objective I will determine howSrebp2suppressesBmp2transcription in the RPE. Objective 2 will further elucidate the mechanism by which RPE-derived BMP2 molecules signal to the other ocular tissues to achieve eye size control. Objective 3 will examine the level/activity changes of theSrebp2-Bmp2pathway in the animal model of myopia and whether the dysregulation of this pathway leads to myopia development. We believe that the outcome of this study will contribute to a better understanding of eye growth control mechanisms in animals as well as point out new molecular and cellular targets for anti-myopia therapies.   

Detail(s)

Project number9043298
Grant typeGRF
StatusNot started
Effective start/end date1/01/23 → …