Yang Sun, MD, PhD

All Publications

• An Open-Label Phase Ib Study to Evaluate Retinal Imaging After Short-term Use of the Balance Goggles System (BGS) in Patients with Glaucoma Li, Z., Knasel, C., Nunez, M., Beykin, G., Goldstein, A., Fisher, A. C., Singh, K., Sun, Y., Chang, R. T., Lee, W., Goldberg, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528303047

• Comparison of Virtual Reality (PalmScan VF2000) Visual Fields Analyzer with Humphrey Visual Field in Glaucoma Patients Tran, E., Wan, L., Yan, W., Sun, Y., Chang, R. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528302143

• Optogenetic stimulation of phosphoinositides reveals a critical role of primary cilia in eye pressure regulation SCIENCE ADVANCES Prosseda, P. P., Alvarado, J. A., Wang, B., Kowal, T. J., Ning, K., Stamer, W., Hu, Y., Sun, Y. 2020; 6 (18)

  View details for DOI 10.1126/sciadv.aay8699

  View details for Web of Science ID 000531089700011

• Optogenetic stimulation of phosphoinositides reveals a critical role of primary cilia in eye pressure regulation. Science advances Prosseda, P. P., Alvarado, J. A., Wang, B., Kowal, T. J., Ning, K., Stamer, W. D., Hu, Y., Sun, Y. 2020; 6 (18): eaay8699

  Abstract

  Glaucoma is a group of progressive optic neuropathies that cause irreversible vision loss. Although elevated intraocular pressure (IOP) is associated with the development and progression of glaucoma, the mechanisms for its regulation are not well understood. Here, we have designed CIBN/CRY2-based optogenetic constructs to study phosphoinositide regulation within distinct subcellular compartments. We show that stimulation of CRY2-OCRL, an inositol 5-phosphatase, increases aqueous humor outflow and lowers IOP in vivo, which is caused by a calcium-dependent actin rearrangement of the trabecular meshwork cells. Phosphoinositide stimulation also rescues defective aqueous outflow and IOP in a Lowe syndrome mouse model but not in IFT88fl/fl mice that lack functional cilia. Thus, our study is the first to use optogenetics to regulate eye pressure and demonstrate that tight regulation of phosphoinositides is critical for aqueous humor homeostasis in both normal and diseased eyes.

  View details for DOI 10.1126/sciadv.aay8699

  View details for PubMedID 32494665

  View details for PubMedCentralID PMC7190330

• Mouse gamma-Synuclein Promoter-Mediated Gene Expression and Editing in Mammalian Retinal Ganglion Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience Wang, Q., Zhuang, P. S., Huang, H., Li, L., Liu, L., Webber, H. C., Dalal, R., Siew, L., Fligor, C. M., Chang, K. C., Nahmou, M., Kreymerman, A., Sun, Y., Meyer, J. S., Goldberg, J. L., Hu, Y. 2020

  Abstract

  Optic neuropathies are a group of optic nerve (ON) diseases caused by various insults including glaucoma, inflammation, ischemia, trauma and genetic deficits, which are characterized by retinal ganglion cell (RGC) death and ON degeneration. An increasing number of genes involved in RGC intrinsic signaling have been found to be promising neural repair targets that can potentially be modulated directly by gene therapy, if we can achieve RGC specific gene targeting. To address this challenge, we first used adeno associated virus (AAV)-mediated gene transfer to perform a low throughput in vivo screening in both male and female mouse eyes and identified the mouse γ-synuclein (mSncg) promoter, which specifically and potently sustained transgene expression in mouse RGCs and also works in human RGCs. We further demonstrated that gene therapy that combines AAV-mSncg promoter with CRISPR/Cas9 gene editing can knockdown pro-degenerative genes in RGCs and provide effective neuroprotection in optic neuropathies.Significance Statement:Here we present an RGC-specific promoter, mouse γ-synuclein (mSncg) promoter, and perform extensive characterization and proof-of-concept studies of mSncg promoter-mediated gene expression and CRISPR/Cas9 gene editing in RGCs in vivo To our knowledge, this is the first report demonstrating in vivo neuroprotection of injured RGCs and optic nerve by AAV-mediated CRISPR/Cas9 inhibition of genes that are critical for neurodegeneration. It represents a powerful tool to achieve RGC-specific gene modulation, and also opens up a promising gene therapy strategy for optic neuropathies, the most common form of eye diseases that cause irreversible blindness.

  View details for DOI 10.1523/JNEUROSCI.0102-20.2020

  View details for PubMedID 32300046

• Longitudinal Morphological and Functional Assessment of RGC Neurodegeneration After Optic Nerve Crush in Mouse. Frontiers in cellular neuroscience Li, L., Huang, H., Fang, F., Liu, L., Sun, Y., Hu, Y. 2020; 14: 109

  Abstract

  The mouse optic nerve crush (ONC) model has been widely used to study optic neuropathies and central nervous system (CNS) axon injury and repair. Previous histological studies of retinal ganglion cell (RGC) somata in retina and axons in ON demonstrate significant neurodegeneration after ONC, but longitudinal morphological and functional assessment of RGCs in living animals is lacking. It is essential to establish these assays to provide more clinically relevant information for early detection and monitoring the progression of CNS neurodegeneration. Here, we present in vivo data gathered by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and pattern electroretinogram (PERG) at different time points after ONC in mouse eyes and corresponding histological quantification of the RGC somata and axons. Not surprisingly, direct visualization of RGCs by SLO fundus imaging correlated best with histological quantification of RGC somata and axons. Unexpectedly, OCT did not detect obvious retinal thinning until late time points (14 and 28-days post ONC) and instead detected significant retinal swelling at early time points (1-5 days post-ONC), indicating a characteristic initial retinal response to ON injury. PERG also demonstrated an early RGC functional deficit in response to ONC, before significant RGC death, suggesting that it is highly sensitive to ONC. However, the limited progression of PERG deficits diminished its usefulness as a reliable indicator of RGC degeneration.

  View details for DOI 10.3389/fncel.2020.00109

  View details for PubMedID 32410964

  View details for PubMedCentralID PMC7200994

• Developmental Distribution of Primary Cilia in the Retinofugal Visual Pathway. The Journal of comparative neurology Alvarado, J. A., Dhande, O. S., Prosseda, P. P., Kowal, T. J., Ning, K., Jabbehdari, S., Hu, Y., Sun, Y. 2020

  Abstract

  The mammalian visual system is composed of circuitry connecting sensory input from the retina to the processing core of the visual cortex. The two main retinorecipient brain targets, the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN), bridge retinal input and visual output. The primary cilium is a conserved organelle increasingly viewed as a critical sensor for the regulation of developmental and homeostatic pathways in most mammalian cell types. Moreover, cilia have been described as crucial for neurogenesis, neuronal maturation, and survival in the cortex and retina. However, cilia in the visual relay center remain to be fully described. In this study, we characterized the ciliation profile of the SC and dLGN and found that the overall number of ciliated cells declined during development. Interestingly, shorter ciliated cells in both regions were identified as neurons, whose numbers remained stable over time, suggesting that cilia retention is a critical feature for optimal neuronal function in SC and dLGN. Our study suggests that primary cilia are important for neuronal maturation and function in cells of the SC and dLGN.

  View details for DOI 10.1002/cne.25029

  View details for PubMedID 32939774

• Oculocerebrorenal syndrome of Lowe: Survey of ophthalmic presentations and management. European journal of ophthalmology Ma, X., Ning, K., Jabbehdari, S., Prosseda, P. P., Hu, Y., Shue, A., Lambert, S. R., Sun, Y. 2020: 1120672120920544

  View details for DOI 10.1177/1120672120920544

  View details for PubMedID 32340490

• A Reversible Silicon Oil-Induced Ocular Hypertension Model in Mice. Journal of visualized experiments : JoVE Zhang, J., Fang, F., Li, L., Huang, H., Webber, H. C., Sun, Y., Mahajan, V. B., Hu, Y. 2019

  Abstract

  Elevated intraocular pressure (IOP) is a well-documented risk factor for glaucoma. Here we describe a novel, effective method for consistently inducing stable IOP elevation in mice that mimics the post-operative complication of using silicone oil (SO) as a tamponade agent in human vitreoretinal surgery. In this protocol, SO is injected into the anterior chamber of the mouse eye to block the pupil and prevent inflow of aqueous humor. The posterior chamber accumulates aqueous humor and this in turn increases the IOP of the posterior segment. A single SO injection produces reliable, sufficient, and stable IOP elevation, which induces significant glaucomatous neurodegeneration. This model is a true replicate of secondary glaucoma in the eye clinic. To further mimic the clinical setting, SO can be removed from the anterior chamber to reopen the drainage pathway and allow inflow of aqueous humor, which is drained through the trabecular meshwork (TM) at the angle of the anterior chamber. Because IOP quickly returns to normal, the model can be used to test the effect of lowering IOP on glaucomatous retinal ganglion cells. This method is straightforward, does not require special equipment or repeat procedures, closely simulates clinical situations, and may be applicable to diverse animal species. However, minor modifications may be required.

  View details for DOI 10.3791/60409

  View details for PubMedID 31789319

• A novel inducible and reversible mouse glaucoma model: Silicone Oil-Induced Ocular Hypertension Under-detected (SOHU) Zhang, J., Li, L., Huang, H., Webber, H., Li, S., Tang, P., Mahajan, V. B., Sun, Y., Zhang, M., Hu, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628101260

• Neuroprotection of Retinal Ganglion Cells by AAV2-gamma-Synuclein Promoter-Mediated CRISPR/Cas9 Gene Editing Li, L., Wang, Q., Huang, H., Sun, Y., Goldberg, J. L., Hu, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628105194

• The Role of Phosphoinositides in Aqueous Humor Dynamics via Optogenetic Stimulation in the Trabecular Meshwork Alvarado, J., Prosseda, P., Ning, K., Kowal, T., Wang, B., Hu, Y., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800704083

• Role of inositol phosphatase OCRL in microtubule nucleation: Implications for Oculocerebrorenal Syndrome of Lowe Kowal, T., Wang, B., Prosseda, P., Alvarado, J., He, W., Ning, K., Hu, Y., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800703274

• Characterization of primary cilia in mouse retina during retinal development Ning, K., Kowal, T., Chang, K., Alvarado, J., Silva, R., Kreymerman, A., Mahajan, V. B., Hu, Y., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800706182

• Oculocerebrorenal Syndrome of Lowe: Characterizations of Ocular Presentation and Management Ma, X., Ning, K., Kowal, T., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628102299

• Ocular and systemic presentations of phosphoinositide signaling defects Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628100011

• Silicone oil-induced ocular hypertension and glaucomatous neurodegeneration in mouse ELIFE Zhang, J., Li, L., Huang, H., Fang, F., Webber, H. C., Zhuang, P., Liu, L., Dalal, R., Tang, P. H., Mahajan, V. B., Sun, Y., Li, S., Zhang, M., Goldberg, J. L., Hu, Y. 2019; 8

  View details for DOI 10.7554/eLife.45881

  View details for Web of Science ID 000468863200001

• Silicone oil-induced ocular hypertension and glaucomatous neurodegeneration in mouse. eLife Zhang, J., Li, L., Huang, H., Fang, F., Webber, H. C., Zhuang, P., Liu, L., Dalal, R., Tang, P. H., Mahajan, V. B., Sun, Y., Li, S., Zhang, M., Goldberg, J. L., Hu, Y. 2019; 8

  Abstract

  Understanding the molecular mechanism of glaucoma and development of neuroprotectants are significantly hindered by the lack of a reliable animal model that accurately recapitulates human glaucoma. Here we sought to develop a mouse model for the secondary glaucoma that is often observed in humans after silicone oil (SO) blocks the pupil or migrates into the anterior chamber following vitreoretinal surgery. We observed significant intraocular pressure (IOP) elevation after intracameral injection of SO, and that SO removal allows IOP to return quickly to normal. This simple, inducible and reversible mouse ocular hypertension model shows dynamic changes of visual function that correlate with progressive RGC loss and axon degeneration. It may be applicable with only minor modifications to a range of animal species in which it will generate stable, robust IOP elevation and significant neurodegeneration that will facilitate selection of neuroprotectants and investigating the pathogenesis of ocular hypertension-induced glaucoma.

  View details for PubMedID 31090540

• AKT-dependent and -independent pathways mediate PTEN deletion-induced CNS axon regeneration. Cell death & disease Huang, H., Miao, L., Yang, L., Liang, F., Wang, Q., Zhuang, P., Sun, Y., Hu, Y. 2019; 10 (3): 203

  Abstract

  Phosphatase and tensin homolog (PTEN) acts as a brake for the phosphatidylinositol 3-kinase-AKT-mTOR complex 1 (mTORC1) pathway, the deletion of which promotes potent central nervous system (CNS) axon regeneration. Previously, we demonstrated that AKT activation is sufficient to promote CNS axon regeneration to a lesser extent than PTEN deletion. It is still questionable whether AKT is entirely responsible for the regenerative effect of PTEN deletion on CNS axons. Here, we show that blocking AKT or its downstream effectors, mTORC1 and GSK3beta, significantly reduces PTEN deletion-induced mouse optic nerve regeneration, indicating the necessary role of AKT-dependent signaling. However, AKT is only marginally activated in PTEN-null mice due to mTORC1-mediated feedback inhibition. That combining PTEN deletion with AKT overexpression or GSK3beta deletion achieves significantly more potent axonal regeneration suggests an AKT-independent pathway for axon regeneration. Elucidating the AKT-independent pathway is required to develop effective strategies for CNS axon regeneration.

  View details for PubMedID 30814515

• Review of Ocular Manifestations of Joubert Syndrome. Genes Wang, S. F., Kowal, T. J., Ning, K., Koo, E. B., Wu, A. Y., Mahajan, V. B., Sun, Y. 2018; 9 (12)

  Abstract

  Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic "molar tooth" sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations.

  View details for PubMedID 30518138

• Considerations for ophthalmic applications of optogenetics ACTA OPHTHALMOLOGICA Wood, E. H., Kreymerman, A., Sun, Y., Drenser, K. A., Trese, M. T. 2018; 96 (8): E1037

  View details for PubMedID 29855158

• Coordination of Necessary and Permissive Signals by PTEN Inhibition for CNS Axon Regeneration FRONTIERS IN NEUROSCIENCE Zhang, J., Yang, D., Huang, H., Sun, Y., Hu, Y. 2018; 12

  View details for DOI 10.3389/fnins.2018.00558

  View details for Web of Science ID 000441431700001

• The role of inositol phosphatase OCRL in microtubule nucleation: Implications for Oculocerebrorenal Syndrome of Lowe Wang, B., Prosseda, P. P., He, W., Kowal, T., Alvarado, J. A., Ning, K., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912509107

• Ocular and renal phenotypes of NPHP1 deletion in Senior Loken syndrome Ning, K., Song, E., Haider, K. M., Ghaffarieh, A., Alvarado, J. A., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932805425

• Optogenetic Regulation of Aqueous Outflow in Mouse Trabecular Meshwork Alvarado, J. A., Prosseda, P. P., Luo, N., Wang, B., Ning, K., He, W., Kowal, T., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932804178

• Single particle tracking of nicotinic acetylcholine receptors (AChRs): implication for the pathogenesis of ocular myasthenia gravis (MG) He, W., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912500291

• Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography JOURNAL OF GLAUCOMA Alvarado, J. A., Srivastava, V., Sun, Y. 2018; 27 (3): E68–E71

  Abstract

  To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT).Fifteen TS in 11 patients diagnosed with primary open-angle, neovascular, aphakic, and uveitic glaucomas. Both Ahmed (n=11) and Baerveldt (n=4) TS were examined with 5-line raster anterior segment SD-OCT imaging.The exposed tubes of 2 patients had highly reflective intraluminal deposits in the corresponding exposed areas. Seven tubes without exposure had a thin rim of highly reflective material. Six tubes were clear of luminal deposits. The most common diagnosis in the study was uveitic glaucoma which occurred in 5 of the 15 eyes (33%). The next most common diagnosis was primary open-angle glaucoma which occurred in 4 of the 15 eyes (25%). There were 2 nonvalved Baerveldt tubes in each group. The mean duration of TS implantation was 15.0 months in the deposit group and 33.7 months in the group without luminal deposits. The majority of patients in each group were using eye drops at presentation (88.9% deposit, 83.3% clear), and the average intraocular pressure was 20.2 mm Hg in the deposit group and 19.0 mm Hg in the clear group.Anterior segment OCT imaging may be used to evaluate TS integrity. Intraluminal deposits in TS may occur as a natural response to implanted drainage device, possibly as an inflammatory response.

  View details for PubMedID 29240598

  View details for PubMedCentralID PMC5831525

• Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic-and oxidative stress-related diseases PLOS ONE Velez, G., Machlab, D. A., Tang, P. H., Sun, Y., Tsang, S. H., Bassuk, A. G., Mahajan, V. B. 2018; 13 (2): e0193250

  Abstract

  Differences in regional protein expression within the human retina may explain molecular predisposition of specific regions to ophthalmic diseases like age-related macular degeneration, cystoid macular edema, retinitis pigmentosa, and diabetic retinopathy. To quantify protein levels in the human retina and identify patterns of differentially-expressed proteins, we collected foveomacular, juxta-macular, and peripheral retina punch biopsies from healthy donor eyes and analyzed protein content by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression was analyzed with 1-way ANOVA, gene ontology, pathway representation, and network analysis. We identified a mean of 1,974 proteins in the foveomacular retina, 1,999 in the juxta-macular retina, and 1,779 in the peripheral retina. Six hundred ninety-seven differentially-expressed proteins included those unique to and abundant in each anatomic region. Proteins with higher expression in each region include: heat-shock protein 90-alpha (HSP90AA1), and pyruvate kinase (PKM) in the foveomacular retina; vimentin (VIM) and fructose-bisphosphate aldolase C (ALDOC); and guanine nucleotide-binding protein subunit beta-1 (GNB1) and guanine nucleotide-binding protein subunit alpha-1 (GNAT1) in the peripheral retina. Pathway analysis identified downstream mediators of the integrin signaling pathway to be highly represented in the foveomacular region (P = 6.48 e-06). Metabolic pathways were differentially expressed among all retinal regions. Gene ontology analysis showed that proteins related to antioxidant activity were higher in the juxta-macular and the peripheral retina, but present in lower amounts in the foveomacular retina. Our proteomic analysis suggests that certain retinal regions are susceptible to different forms of metabolic and oxidative stress. The findings give mechanistic insight into retina function, reveal important molecular processes, and prioritize new pathways for therapeutic targeting.

  View details for PubMedID 29466423

• Coordination of Necessary and Permissive Signals by PTEN Inhibition for CNS Axon Regeneration. Frontiers in neuroscience Zhang, J., Yang, D., Huang, H., Sun, Y., Hu, Y. 2018; 12: 558

  Abstract

  In the nearly 10 years since PTEN was identified as a prominent intrinsic inhibitor of CNS axon regeneration, the PTEN negatively regulated PI3K-AKT-mTOR pathway has been intensively explored in diverse models of axon injury and diseases and its mechanism for axon regeneration is becoming clearer. It is therefore timely to summarize current knowledge and discuss future directions of translational regenerative research for neural injury and neurodegenerative diseases. Using mouse optic nerve crush as an in vivo retinal ganglion cell axon injury model, we have conducted an extensive molecular dissection of the PI3K-AKT pathway to illuminate the cross-regulating mechanisms in axon regeneration. AKT is the nodal point that coordinates both positive and negative signals to regulate adult CNS axon regeneration through two parallel pathways, activating mTORC1 and inhibiting GSK3ββ. Activation of mTORC1 or its effector S6K1 alone can only slightly promote axon regeneration, whereas blocking mTORC1 significantly prevent axon regeneration, suggesting the necessary role of mTORC1 in axon regeneration. However, mTORC1/S6K1-mediated feedback inhibition prevents potent AKT activation, which suggests a key permissive signal from an unidentified AKT-independent pathway is required for stimulating the neuron-intrinsic growth machinery. Future studies into this complex neuron-intrinsic balancing mechanism involving necessary and permissive signals for axon regeneration is likely to lead eventually to safe and effective regenerative strategies for CNS repair.

  View details for PubMedID 30158848

  View details for PubMedCentralID PMC6104488

• Neuroprotection by eIF2 alpha-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss CELL DEATH & DISEASE Huang, H., Miao, L., Liang, F., Liu, X., Xu, L., Teng, X., Wang, Q., Ridder, W. H., Shindler, K. S., Sun, Y., Hu, Y. 2017; 8: e2936

  Abstract

  No therapies exist to prevent neuronal deficits in multiple sclerosis (MS), because the molecular mechanism responsible for the progressive neurodegeneration is unknown. We previously showed that axon injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death and optic nerve degeneration in traumatic and glaucomatous optic neuropathies. Optic neuritis, one of the most common clinical manifestations of MS, is readily modeled by experimental autoimmune encephalomyelitis (EAE) in mouse. Using this in vivo model, we now show that ER stress is induced early in EAE and that modulation of ER stress by inhibition of eIF2α-CHOP and activation of XBP-1 in RGC specifically, protects RGC somata and axons and preserves visual function. This finding adds to the evidence that ER stress is a general upstream mechanism for neurodegeneration and suggests that targeting ER stress molecules is a promising therapeutic strategy for neuroprotection in MS.

  View details for PubMedID 28726788

• Occult lens subluxation related to laser peripheral iridotomy A case report and literature review MEDICINE Hu, R., Wang, X., Wang, Y., Sun, Y. 2017; 96 (10)

  Abstract

  Laser peripheral iridotomy (LPI) is commonly performed as a primary treatment for acute primary angle closure glaucoma after administration of anti-glaucoma medications or for prevention of this condition. Minor complications may occur following LPI and most of them do not have deleterious consequences. We report a rare case of lens subluxation that has a possible relationship with LPI treatment.A 54-year-old female patient was initially referred for surgical treatment of medication-uncontrollable angle closure glaucoma in her left eye. The patient had undergone Neodymium:YAG LPI at an outside hospital 2 months prior to the presentation due to an episode of elevated intraocular pressure (IOP). About 5 days after the LPI, she had spontaneous blurred vision, redness, and pain in the left eye. Her IOP was found to re-rise and was not controlled well even with maximum tolerated anti-glaucoma medications during the following 2 months. On slit-lamp examination, the significant shallowing of both peripheral and central anterior chamber was noted in the left eye. Ultrasound biomicroscopy examination revealed the lens tilting towards the iris and the inferior zonular dehiscence corresponding to the iridotomy site.Lens subluxation secondary to LPI treatment in the left eye.Phacoemulsification combined with in-the-bag intraocular lens implantation was performed in the left eye. The zonular weakness corresponding to the iridotomy site was further confirmed during surgery.The patient's IOP remained stable in the first postoperative 3 months without additional anti-glaucoma medications.Laser peripheral iridotomy may cause structural zonular damage, and ophthalmologists should be aware of this potential complication and proceed with caution.

  View details for DOI 10.1097/MD.0000000000006255

  View details for Web of Science ID 000396041000038

  View details for PubMedID 28272229

• Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. Journal of cell science Prosseda, P. P., Luo, N., Wang, B., Alvarado, J. A., Hu, Y., Sun, Y. 2017; 130 (20): 3447–54

  Abstract

  Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.

  View details for PubMedID 28871046

• Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis. Scientific reports Song, E., Luo, N., Alvarado, J. A., Lim, M., Walnuss, C., Neely, D., Spandau, D., Ghaffarieh, A., Sun, Y. 2017; 7 (1): 1442

  Abstract

  Mutations in the OCRL1 gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and neurological impairments. OCRL1 encodes an inositol polyphosphate 5-phosphatase which preferentially dephosphorylates phosphatidylinositide 4,5 bisphosphate (PI(4,5)P2). We have identified two novel mutations in two unrelated Lowe syndrome patients with congenital glaucoma. Novel deletion mutations are detected at c.739-742delAAAG in Lowe patient 1 and c.1595-1631del in Lowe patient 2. End stage glaucoma in patient 2 resulted in the enucleation of the eye, which on histology demonstrated corneal keloid, fibrous infiltration of the angle, ectropion uvea, retinal gliosis, and retinal ganglion cell loss. We measured OCRL protein levels in patient keratinocytes and found that Lowe 1 patient cells had significantly reduced OCRL protein as compared to the control keratinocytes. Genotype-phenotype correlation of OCRL1 mutations associated with congenital glaucoma revealed clustering of missense and deletion mutations in the 5-phosphatase domain and the RhoGAP-like domain. In conclusion, we report novel OCRL1 mutations in Lowe syndrome patients and the corresponding histopathologic analysis of one patient's ocular pathology.

  View details for PubMedID 28473699

  View details for PubMedCentralID PMC5431454

• Primary cilia signaling mediates intraocular pressure sensation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Luo, N., Conwell, M. D., Chen, X., Kettenhofen, C. I., Westlake, C. J., Cantor, L. B., Wells, C. D., Weinreb, R. N., Corson, T. W., Spandau, D. F., Joos, K. M., Iomini, C., Obukhov, A. G., Sun, Y. 2014; 111 (35): 12871-12876

  Abstract

  Lowe syndrome is a rare X-linked congenital disease that presents with congenital cataracts and glaucoma, as well as renal and cerebral dysfunction. OCRL, an inositol polyphosphate 5-phosphatase, is mutated in Lowe syndrome. We previously showed that OCRL is involved in vesicular trafficking to the primary cilium. Primary cilia are sensory organelles on the surface of eukaryotic cells that mediate mechanotransduction in the kidney, brain, and bone. However, their potential role in the trabecular meshwork (TM) in the eye, which regulates intraocular pressure, is unknown. Here, we show that TM cells, which are defective in glaucoma, have primary cilia that are critical for response to pressure changes. Primary cilia in TM cells shorten in response to fluid flow and elevated hydrostatic pressure, and promote increased transcription of TNF-α, TGF-β, and GLI1 genes. Furthermore, OCRL is found to be required for primary cilia to respond to pressure stimulation. The interaction of OCRL with transient receptor potential vanilloid 4 (TRPV4), a ciliary mechanosensory channel, suggests that OCRL may act through regulation of this channel. A novel disease-causing OCRL allele prevents TRPV4-mediated calcium signaling. In addition, TRPV4 agonist GSK 1016790A treatment reduced intraocular pressure in mice; TRPV4 knockout animals exhibited elevated intraocular pressure and shortened cilia. Thus, mechanotransduction by primary cilia in TM cells is implicated in how the eye senses pressure changes and highlights OCRL and TRPV4 as attractive therapeutic targets for the treatment of glaucoma. Implications of OCRL and TRPV4 in primary cilia function may also shed light on mechanosensation in other organ systems.

  View details for DOI 10.1073/pnas.1323292111

  View details for Web of Science ID 000341230800077

  View details for PubMedID 25143588

• STAT6-Mediated Keratitis and Blepharitis: A Novel Murine Model of Ocular Atopic Dermatitis INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Turner, M. J., DaSilva-Arnold, S., Luo, N., Hu, X., West, C. C., Sun, L., Hall, C., Bradish, J., Kaplan, M. H., Travers, J. B., Sun, Y. 2014; 55 (6): 3803-3808

  Abstract

  Atopic dermatitis (AD) is a common inflammatory disease that can affect the eye, resulting in ocular pathologies, including blepharitis, keratitis, and uveitis; however, the pathogenic mechanisms underlying the ocular manifestations of AD are not well understood.In the present study, we characterized the ocular pathologies that develop in the Stat6VT mouse model of AD. We examined the cytokine profile of the eyelid lesions, measured the behavioral response, and documented the treatment response to topical steroids.Our results show that Stat6VT mice spontaneously developed blepharitis, keratitis, and uveitis similar to that observed in patients with AD. Histologic findings of allergic inflammation in affected eyelids in this model include the presence of a lymphocyte-predominant infiltrate and tissue eosinophilia in the dermis. Gene expression analysis of affected eyelid tissue by quantitative PCR revealed increased amounts of mRNAs for the Th2 cytokines IL-4, IL-5, and IL-13. In addition, increased eyelid scratching was seen in Stat6VT mice with blepharitis. Topical treatment with the corticosteroid clobetasol reduced eyelid inflammation, tissue eosinophilia, and Th2 cytokine expression.The development of AD-like ocular pathologies in this model supports the idea that in humans, AD-associated disease of the eye may be driven by Th2-mediated inflammation and demonstrates that the Stat6VT mouse may be a useful system in which to further investigate pathogenesis of and treatment strategies for blepharitis and other ocular diseases that develop in association with AD.

  View details for DOI 10.1167/iovs.13-13685

  View details for Web of Science ID 000339485800053

  View details for PubMedID 24845637

• Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Adler, J. J., Johnson, D. E., Heller, B. L., Bringman, L. R., Ranahan, W. P., Conwell, M. D., Sun, Y., Hudmon, A., Wells, C. D. 2013; 110 (43): 17368-17373

  Abstract

  Large tumor suppressor (LATS)1/2 protein kinases transmit Hippo signaling in response to intercellular contacts and serum levels to limit cell growth via the inhibition of Yes-associated protein (YAP). Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130. Consistently, the Amot130 (S175A) mutant, which lacks LATS phosphorylation, bound AIP4 poorly under all conditions and showed reduced stability. Amot130 and AIP4 also promoted the ubiquitination and degradation of YAP in response to serum starvation, unlike Amot130 (S175A). Moreover, silencing Amot130 expression blocked LATS1 from inhibiting the expression of connective tissue growth factor, a YAP-regulated gene. Concordant with phosphorylated Amot130 specifically mediating these effects, wild-type Amot130 selectively induced YAP phosphorylation and reduced transcription of connective tissue growth factor in an AIP4-dependent manner versus Amot130 (S175A). Further, Amot130 but not Amot130 (S175A) strongly inhibited the growth of MDA-MB-468 breast cancer cells. The dominant-negative effects of Amot130 (S175A) on YAP signaling also support that phosphorylated Amot130 transduces Hippo signaling. Likewise, Amot130 expression provoked premature growth arrest during mammary cell acini formation, whereas Amot130 (S175A)-expressing cells formed enlarged and poorly differentiated acini. Taken together, the phosphorylation of Amot130 by LATS is found to be a key feature that enables it to inhibit YAP-dependent signaling and cell growth.

  View details for DOI 10.1073/pnas.1308236110

  View details for Web of Science ID 000325943300050

  View details for PubMedID 24101513

• Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe PLOS ONE Luo, N., Kumar, A., Conwell, M., Weinreb, R. N., Anderson, R., Sun, Y. 2013; 8 (6)

  Abstract

  Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm's canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer's vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.

  View details for DOI 10.1371/journal.pone.0066727

  View details for Web of Science ID 000320846500099

  View details for PubMedID 23805271

• Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish VISION RESEARCH Luo, N., Lu, J., Sun, Y. 2012; 75: 98-107

  Abstract

  Inositol phosphatases are important regulators of cell signaling and membrane trafficking. Mutations in inositol polyphosphate 5-phosphatase, INPP5E, have been identified in Joubert syndrome, a rare congenital disorder characterized by midbrain malformation, retinitis pigmentosa, renal cysts, and polydactyly. Previous studies have implicated primary cilia abnormalities in Joubert syndrome, yet the role of INPP5E in cilia formation is not well understood. In this study, we examined the function of INPP5E in cilia development in zebrafish. Using specific antisense morpholino oligonucleotides to knockdown Inpp5e expression, we observed phenotypes of microphthalmia, pronephros cysts, pericardial effusion, and left-right body axis asymmetry. The Inpp5e morphant zebrafish exhibited shortened and decreased cilia formation in the Kupffer's vesicle and pronephric ducts as compared to controls. Epinephrine-stimulated melanosome trafficking was delayed in the Inpp5e zebrafish morphants. Expression of human INPP5E expression rescued the phenotypic defects in the Inpp5e morphants. Taken together, we showed that INPP5E is critical for the cilia development in zebrafish.

  View details for DOI 10.1016/j.visres.2012.09.011

  View details for Web of Science ID 000312426100015

  View details for PubMedID 23022135

• OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome HUMAN MOLECULAR GENETICS Luo, N., West, C. C., Murga-Zamalloa, C. A., Sun, L., Anderson, R. M., Wells, C. D., Weinreb, R. N., Travers, J. B., Khanna, H., Sun, Y. 2012; 21 (15): 3333-3344

  Abstract

  Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia-dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome.

  View details for DOI 10.1093/hmg/dds163

  View details for Web of Science ID 000306414900003

  View details for PubMedID 22543976

• p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb-Hdm2 interaction and apoptosis ONCOGENE Delston, R. B., Matatall, K. A., Sun, Y., Onken, M. D., Harbour, J. W. 2011; 30 (5): 588-599

  Abstract

  The retinoblastoma protein (Rb) inhibits both cell division and apoptosis, but the mechanism by which Rb alternatively regulates these divergent outcomes remains poorly understood. Cyclin-dependent kinases (Cdks) promote cell division by phosphorylating and reversibly inactivating Rb by a hierarchical series of phosphorylation events and sequential conformational changes. The stress-regulated mitogen-activated protein kinase p38 also phosphorylates Rb, but it does so in a cell cycle-independent manner that is associated with apoptosis rather than with cell division. Here, we show that p38 phosphorylates Rb by a novel mechanism that is distinct from that of Cdks. p38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates Rb on Ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not Cdks, triggers an interaction between Rb and the human homolog of murine double minute 2 (Hdm2), leading to degradation of Rb, release of E2F1 and cell death. These findings provide a mechanistic explanation as to how Rb regulates cell division and apoptosis through different kinases, and reveal how Hdm2 may functionally link the tumor suppressors Rb and p53.

  View details for DOI 10.1038/onc.2010.442

  View details for Web of Science ID 000286922300007

  View details for PubMedID 20871633

• Functional analysis of the p53 pathway in response to ionizing radiation in uveal melanoma INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Sun, Y., Tran, B. N., Worley, L. A., Delston, R. B., Harbour, J. W. 2005; 46 (5): 1561-1564

  Abstract

  Uveal melanomas are notoriously radioresistant and thus necessitate treatment with extremely high radiation doses that often cause ocular complications. The p53 tumor suppressor pathway is a major mediator of the cellular response to radiation-induced DNA damage, suggesting that this pathway may be defective in uveal melanoma. The current study was conducted to analyze the functional integrity of the p53 pathway in primary uveal melanoma cells.The p53 gene was sequenced in three primary uveal melanoma cells lines. Cultured primary uveal melanoma cells (MM28, MM50, Mel202, Mel270, and Mel290), MCF7 breast carcinoma cells, normal uveal melanocytes (UM47), and normal human diploid fibroblasts (NHDFs) were irradiated at 250 kVp and 12 mA at a dose rate of 1.08 Gy/min for a total dose of up to 20 Gy. Cell viability was analyzed with trypan blue exclusion. Western blot analysis was used to analyze the expression of p53, p53-phospho-Ser15, p21, Bax, PUMA, and Bcl-x(L).No p53 gene mutations were found in MM28, MM50, or Mel270 cells. Upstream signaling to p53 was intact, with normal induction of p53 and phosphorylation of p53-Ser15, in all five cell lines. Radiation-induced downstream activation of p21 was defective in MM28 and MM50 cells, and activation of Bax was defective in MM50 and Mel290 cells. MM28, MM50, and Mel202 cells failed to deamidate Bcl-x(L) in response to radiation-induced DNA damage. Overall, four of the five uveal melanoma cell lines exhibited at least one downstream defect in the p53 pathway.Expression of p53 and upstream signaling to p53 in response to radiation-induced DNA damage appear to be intact in most uveal melanomas. In contrast, functional defects in the p53 pathway downstream of p53 activation appear to be common. Further elucidation of p53 pathway abnormalities in uveal melanoma may allow therapeutic interventions to increase the radiosensitivity of the tumors.

  View details for DOI 10.1167/iovs.04-1362

  View details for Web of Science ID 000228708000005

  View details for PubMedID 15851551