a-reversible-silicon-oil-induced-ocular-hypertension-model-in-mice

A Reversible Silicon Oil-Induced Ocular Hypertension Model in Mice

Elevated intraocular pressure (IOP) is a well-documented risk factor for glaucoma. Here we describe a novel, effective method for consistently inducing ...

Stanford University School of Medicine

Veterans Affairs Palo Alto Health Care

Hemoglobin (Hb) is known to be associated with both nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS). We evaluated the relationship between serum Hb levels and the development of MS or NAFLD.

Associations between hemoglobin concentrations and the development of incidental metabolic syndrome or nonalcoholic fatty liver disease.

. Chronic low-grade inflammation is thought to be associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). This study aimed to determine the association between serum white blood cell (WBC) counts and the development of incidental NAFLD. . In this retrospective longitudinal cohort study, we recruited participants who underwent abdominal ultrasonography and blood samplings during medical checkups in both 2005 and 2010. A total of 2,216 subjects were included in our analyses. . The prevalence of NAFLD in 2010 increased steadily in conjunction with increasing WBC counts in 2005 after adjustment for body mass index (BMI) [odds ratio (OR) 2.44, 95% confidence interval (CI) = 1.49-4.00 for women and OR 2.42, 95% CI = 1.61-3.63 for men, lowest quartile versus highest quartile]. Multivariate regression analysis after adjusting for age, BMI, hypertension, smoking, triglycerides, HDL cholesterol, and glucose levels revealed that NAFLD was significantly associated with the highest WBC quartile compared to the lowest quartile [OR 1.85, 95% CI, 1.10-3.10 for women and OR 1.68, 95% CI, 1.08-2.61 for men]. . We demonstrated that the risk of developing NAFLD was significantly associated with WBC counts independently of metabolic factors. This finding provides novel evidence indicating that serum WBC counts may be potential surrogate markers of NAFLD.

Associations between White Blood Cell Count and the Development of Incidental Nonalcoholic Fatty Liver Disease.

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)P). 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.

Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis.

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.

Neuroprotection by eIF2α-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss.

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)P, 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)P and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in -null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P 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.

Loss of OCRL increases ciliary PI(4,5)P in Lowe oculocerebrorenal syndrome.

To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT).

Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography.

The aim of this study was to examine the prospective association between visceral obesity and the incidence and recurrence of colorectal adenoma.

Visceral obesity as a risk factor for colorectal adenoma occurrence in surveillance colonoscopy.

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  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.

Coordination of Necessary and Permissive Signals by PTEN Inhibition for CNS Axon Regeneration.

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 GSK3β, 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 GSK3β 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.

AKT-dependent and -independent pathways mediate PTEN deletion-induced CNS axon regeneration.

Understanding the molecular mechanism of glaucoma and development of neuroprotectants is 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 retinal ganglion cell (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.

Yang Sun

Department of Ophthalmology

Stanford University School of Medicine

A Reversible Silicon Oil-Induced Ocular Hypertension Model in Mice

Yang Sun

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Ophthalmology

Stanford University School of Medicine

A Reversible Silicon Oil-Induced Ocular Hypertension Model in Mice

Department of Ophthalmology