A5103156451- Retinal Development and Disorders
- Glaucoma and retinal disorders
- Nerve injury and regeneration
- Retinal Diseases and Treatments
- PI3K/AKT/mTOR signaling in cancer
- Endoplasmic Reticulum Stress and Disease
- Sirtuins and Resveratrol in Medicine
- Thermal Regulation in Medicine
- Traumatic Brain Injury and Neurovascular Disturbances
- Retinoids in leukemia and cellular processes
- Burn Injury Management and Outcomes
- Hereditary Neurological Disorders
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- Cell death mechanisms and regulation
- Ocular Oncology and Treatments
- Axon Guidance and Neuronal Signaling
- RNA regulation and disease
- Retinal and Macular Surgery
- Retinopathy of Prematurity Studies
- Neurological Disorders and Treatments
- Neurogenesis and neuroplasticity mechanisms
- Connexins and lens biology
- Infectious Encephalopathies and Encephalitis
- Winter Sports Injuries and Performance
Stanford University
2017-2025
Vision Eye Institute
2024
Stanford Medicine
2019
Temple University
2014-2016
Temple University Hospital
2016
Shriners Hospitals for Children
2016
Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator PI3K, induces axon regeneration through activation PI3K-mTOR signaling. We have conducted an extensive molecular dissection cross-regulating mechanisms that involve downstream effectors AKT and two mTOR complexes (mTORC1 mTORC2). found predominant isoform CNS, AKT3, much more robust than AKT1 mTORC1 inhibition GSK3β are critical parallel pathways for AKT-induced regeneration. Surprisingly,...
The lack of neuroprotective treatments for retinal ganglion cells (RGCs) and optic nerve (ON) is a central challenge glaucoma management. Emerging evidence suggests that redox factor NAD+ decline hallmark aging neurodegenerative diseases. Supplementation with precursors overexpression NMNAT1, the key enzyme in biosynthetic process, have significant effects. We first profile translatomes RGCs naive mice silicone oil-induced ocular hypertension (SOHU)/glaucoma by RiboTag mRNA sequencing....
Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital functions. The connection these two obviously sequential degenerative events, however, elusive. Deciphering the upstream signals trigger neurodegeneration cascades both soma axon would be a key step toward developing effective neuroprotectants are greatly needed clinic. We showed previously optic nerve injury-induced endoplasmic reticulum (ER)...
Understanding the molecular mechanism of glaucoma and development neuroprotectants is significantly hindered by lack a reliable animal model that accurately recapitulates human glaucoma. Here, we sought to develop mouse for secondary often observed in humans after silicone oil (SO) blocks pupil or migrates into anterior chamber following vitreoretinal surgery. We significant intraocular pressure (IOP) elevation intracameral injection SO, SO removal allows IOP return quickly normal. This...
Optic neuropathies are a group of optic nerve (ON) diseases caused by various insults including glaucoma, inflammation, ischemia, trauma, and genetic deficits, which characterized retinal ganglion cell (RGC) death ON degeneration. An increasing number genes involved in RGC intrinsic signaling have been found to be promising neural repair targets that can potentially modulated directly gene therapy, if we achieve specific targeting. To address this challenge, first used adeno-associated virus...
The mouse optic nerve crush (ONC) model has been widely used to study neuropathies and central nervous system (CNS) axon injury repair. Previous histological studies of retinal ganglion cell (RGC) somata in retina axons ON demonstrate significant neurodegeneration after ONC, but longitudinal morphological functional assessment RGCs living animals is lacking. It essential establish these assays provide more clinically relevant information for early detection monitoring the progression CNS...
Optic neuropathy is a group of optic nerve (ON) diseases with progressive degeneration ON and retinal ganglion cells (RGCs). The lack neuroprotective treatments central challenge for this leading cause irreversible blindness. SARM1 (sterile α TIR motif-containing protein 1) has intrinsic nicotinamide adenine dinucleotide (NAD+) hydrolase activity that causes axon by degrading axonal NAD+ significantly after activation injury. deletion in many, but not all, neurodegenerative disease models....
Abstract No therapies exist to prevent neuronal deficits in multiple sclerosis (MS), because the molecular mechanism responsible for progressive neurodegeneration is unknown. We previously showed that axon injury-induced endoplasmic reticulum (ER) stress plays an important role retinal ganglion cell (RGC) death and optic nerve degeneration traumatic glaucomatous neuropathies. Optic neuritis, one of most common clinical manifestations MS, readily modeled by experimental autoimmune...
Abstract Phosphatase and tensin homolog (PTEN) acts as a brake for the phosphatidylinositol 3-kinase–AKT–mTOR complex 1 (mTORC1) pathway, deletion of which promotes potent central nervous system (CNS) axon regeneration. Previously, we demonstrated that AKT activation is sufficient to promote CNS regeneration lesser extent than PTEN deletion. It still questionable whether entirely responsible regenerative effect on axons. Here, show blocking or its downstream effectors, mTORC1 GSK3β,...
Endoplasmic reticulum (ER) stress has been linked with various acute and chronic neurodegenerative diseases. We previously found that optic nerve (ON) injury diseases induce neuronal ER in retinal ganglion cells (RGCs). further demonstrated germline deletion of CHOP preserves the structure function both RGC somata axons mouse glaucoma models. Here we report RGC-specific and/or its upstream regulator ATF4 synergistically promotes ON survival visual crush silicone oil-induced ocular...
Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, the molecular mechanisms underlying neurodegeneration unknown. We find that OPTN C-terminus truncation (OPTN∆C) causes late-onset of retinal ganglion cells (RGCs), optic nerve (ON), spinal cord motor neurons, preceded by decrease axonal mitochondria in mice. discover directly interacts with both microtubules mitochondrial transport complex...
After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal axon degenerations were previously thought to be controlled by two parallel pathways, involving activation kinase dual leucine-zipper (DLK) loss survival factor nicotinamide mononucleotide adenylyltransferase-2 (NMNAT2), respectively. Here, we report that palmitoylation both DLK NMNAT2 palmitoyl acyltransferase ZDHHC17 couples these signals. ZDHHC17-dependent enables...
Abstract Recently, we established silicone oil-induced ocular hypertension (SOHU) mouse model with significant glaucomatous neurodegeneration. Here characterize two additional variations of this that simulate distinct glaucoma types. The first is a chronic produced by high frequency (HF) pupillary dilation after SO-induced block, which shows sustained moderate IOP elevation and corresponding slow, mild We also demonstrate although SO removal quickly returns to normal, the neurodegeneration...
Elevated intraocular pressure (IOP) is a well-documented risk factor for glaucoma. Here we describe novel, effective method consistently inducing stable IOP elevation in mice that mimics the post-operative complication of using silicone oil (SO) as tamponade agent human vitreoretinal surgery. In this protocol, SO injected into anterior chamber mouse eye to block pupil and prevent inflow aqueous humor. The posterior accumulates humor turn increases segment. A single injection produces...
When the protein or calcium homeostasis of endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion an downstream effector, CHOP, significantly protects neuron somata and axons. Here we report three tricyclic compounds identified through a small-scale high throughput screening using CHOP promoter-driven luciferase cell-based assay, effectively inhibit by antagonizing their common target, histamine...
Purpose: Increased endoplasmic reticulum (ER) stress is one of the earliest subcellular changes in neuro-ophthalmic diseases. In this study, we investigated expression key molecules ER pathways following nonarteritic anterior ischemic optic neuropathy (AION), most common acute adults over 50, and assessed impact chemical chaperon 4-phenylbutyric acid (4-PBA) vivo. Methods: We induced AION using photochemical thrombosis adult mice performed histologic analyses pathway retina nerve. also...
Retinal ganglion cells (RGCs) are heterogeneous projection neurons that convey distinct visual features from the retina to brain. Here, we present a high-throughput in vivo RGC activity assay response light stimulation using noninvasive Ca 2+ imaging of thousands RGCs simultaneously living mice. Population and single-cell analyses longitudinal reveal functional responses unprecedented individual conversions during traumatic glaucomatous degeneration. This study establishes foundation for...
Abstract Optineurin (OPTN) mutations are linked to amyotrophic lateral sclerosis (ALS) and normal tension glaucoma (NTG), but a relevant animal model is lacking, the molecular mechanisms underlying neurodegeneration unknown. We found that OPTN C-terminus truncation (OPTNΔC) causes late-onset of retinal ganglion cells (RGCs), optic nerve (ON), spinal cord motor neurons, preceded by striking decrease axonal mitochondria. Surprisingly, we discover directly interacts with both microtubules...
Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as optic nerve (ON), are deeply buried, preventing access local TH. The alternative to apply TH systemically, which significantly limits applicable temperature range. (2) Even with possible ‘local refrigeration’, cold-induced cellular damage offsets benefit Here...
Previously, we developed a simple procedure of intracameral injection silicone oil (SO) into mouse eyes and established the SOHU (SO-induced ocular hypertension under-detected) glaucoma model with reversible intraocular pressure (IOP) elevation significant glaucomatous neurodegeneration. Because anatomy non-human primate (NHP) visual system closely resembles that humans, it is most likely to predict human responses diseases therapies. Here tried replicate in rhesus macaque monkeys. All six...