Abstract The objectives of our study are to characterize the expression of a novel long noncoding RNA (lncRNA) located in the LOXL1 (lysyl oxidase-like 1) genomic region and to determine its function in relation to exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). XFS is the most common cause of open-angle glaucoma, affecting 3-20% individuals over 70 years of age worldwide. Sequence variants in the LOXL1 genomic region have been associated with XFS and XFG in all ethnic groups. LOXL1 protein has been identified as a component of the exfoliation material. Dysregulation of LOXL1 expression in the anterior segment and lamina cribosa have been identified in patients with XFS and XFG. However, transgenic mouse models with either loss or overexpression of LOXL1 have failed to show any accumulation of exfoliation material or elevated intraocular pressure. It remains unknown how this genomic locus contributes to XFS/XFG. Our preliminary study has identified a novel long noncoding RNA overlapping with part of the coding regions of LOXL1 gene, referred as lncLOXL1. This specific lncLOXL1 is ubiquitously expressed in many human tissues including eye, such as those affected by XFS/XFG (ciliary body, trabecular meshwork, retina, optic nerve, and cornea). Its expression can be regulated by several XFS-related environmental factors, such as TGF-?1. We propose to determine the expression and function of lncLOXL1 in relation to XFS. We will determine how its expression responds to XFS-related environmental factors in a time course and how its expression is different in XFS- affected human ocular tissues (Aim 1). At the same time, we will determine the genes/proteins targeted by lncLOXL1 by lncRNA knockdown in two different cell lines through total RNA-Seq and miRNA-Seq (Aim 2). Successful completion of this proposal will provide critical information on the regulation of lncLOXL1 expression. The identification of target coding and long noncoding genes and miRNAs will advance our understanding of the potential function of this noncoding RNA and its contribution to exfoliation syndrome and glaucoma. The data generated will be used a preliminary data for a NIH R01 application.
- National Eye Institute: $228,500.00
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