Lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) lncRNA differentially regulates gene and protein expression, signaling and morphology of human ocular cells.
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2023-10
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Pseudoexfoliation glaucoma (PEXG) is characterized by dysregulated extracellular matrix (ECM) homeostasis that disrupts conventional outflow function and increases intraocular pressure (IOP). Prolonged IOP elevation results in optic nerve head damage and vision loss. Uniquely, PEXG is a form of open angle glaucoma that has variable penetrance, is difficult to treat and does not respond well to common IOP-lowering pharmaceuticals. Therefore, understanding modulators of disease severity will aid in targeted therapies for PEXG. Genome-wide association studies have identified polymorphisms in the long non-coding RNA lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) as a risk factor for PEXG. Risk alleles, oxidative stress and mechanical stretch all alter LOXL1-AS1 expression. As a long non-coding RNA, LOXL1-AS1 binds hnRNPL and regulates global gene expression. In this study, we focus on the role of LOXL1-AS1 in the ocular cells (trabecular meshwork and Schlemm's canal) that regulate IOP. We show that selective knockdown of LOXL1-AS1 leads to cell-type-specific changes in gene expression, ECM homeostasis, signaling and morphology. These results implicate LOXL1-AS1 as a modulator of cellular homeostasis, altering cell contractility and ECM turnover, both of which are well-known contributors to PEXG. These findings support LOXL1-AS1 as a key target for modifying the disease.
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Schmitt, Heather M, Kristyn M Hake, Kristin M Perkumas, Brandon M Lê, Maria F Suarez, Michael L De Ieso, Rashad S Rahman, William M Johnson, et al. (2023). Lysyl oxidase-like 1-antisense 1 (LOXL1-AS1) lncRNA differentially regulates gene and protein expression, signaling and morphology of human ocular cells. Human molecular genetics, 32(21). pp. 3053–3062. 10.1093/hmg/ddad128 Retrieved from https://hdl.handle.net/10161/30066.
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Scholars@Duke
![Ashley-Koch](https://scholars.duke.edu/profile-images/thumbnail200/0215530.jpg)
Allison Elizabeth Ashley-Koch
My work focuses on the dissection of human traits using multi-omic technologies (genetics, epigenetics, metabolomics and proteomics). I am investigating the basis of several neurological and psychiatric conditions such as neural tube defects and post-traumatic stress disorder. I also study modifiers of sickle cell disease.
![Hauser](https://scholars.duke.edu/profile-images/thumbnail200/0203861.jpg)
Michael Arthur Hauser
Dr. Hauser has a strong interest in ocular genetics. Genomic studies at the Center for Human Genetics have identified multiple linkage peaks and susceptibility genes in primary open angle glaucoma (POAG) and age related macular degeneration (AMD). Dr. Hauser has recently accepted a 20% appointment at the Singapore Eye Research INstitute and the Duke/National University of Singapore. In collaboration with multiple collaborators in Singapore, and Dr. Rand Allingham at the Duke Eye Center, Dr. Hauser is currently conducting a genome wide association study for glaucoma in individuals of African ancestry. These investigations include large datasets collected in Ghana, Nigeria, and South Africa.
Dr. Hauser is also involved in collaborative investigations into the genetics of post-tramatic stress disorder in US veterans from Iraq and Afghanistan. Major collaborators include Dr. Allison Ashley Koch, Dr. Jean Beckham, Dr. Christine Marx and the MIRECC Collaborative group at the Durham Veteran's Administration. We have published a genome wide association study, as well as numerous investigations into candidate genes. Epigenomic DNA methylation analysis and gene expression analysis of 3500 individuals is currently ongoing.
![Stamer](https://scholars.duke.edu/profile-images/thumbnail200/0188763.jpg)
W Daniel Stamer
My laboratory studies the disease of glaucoma, the second leading cause of blindness in the United States, affecting nearly 3 million people (70 million Worldwide). The primary risk factor for developing glaucoma is ocular hypertension (high intraocular pressure, IOP). IOP is a function of the regulated movement of aqueous humor into and out of the eye. Elevated IOP in glaucoma is a result of disease in the primary efflux route, the conventional outflow pathway, affecting proper homeostatic control of aqueous humor drainage.
Lowering IOP in glaucoma patients, whether or not they have ocular hypertension, is important because large clinical trials involving tens of thousands of patients repeatedly demonstrate that significant, sustained IOP reduction slows or halts vision loss. Unfortunately, current first-line medical treatments do not target the diseased conventional pathway and do not lower IOP sufficiently in most people with glaucoma. Therefore, finding new, more effective ways to medically control IOP by targeting the conventional pathway is a central goal the Stamer Laboratory.
Using molecular, cellular, organ and mouse model systems, my laboratory seeks to identify and validate novel drug targets in the human conventional outflow pathway to facilitate the development of the next generation of treatments for ocular hypertension and glaucoma.
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