A5062159085- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Prion Diseases and Protein Misfolding
- Retinoids in leukemia and cellular processes
- Photoreceptor and optogenetics research
- Advanced Fluorescence Microscopy Techniques
- Receptor Mechanisms and Signaling
- CRISPR and Genetic Engineering
- Photochromic and Fluorescence Chemistry
- Cellular transport and secretion
- Neurological diseases and metabolism
- Lipid Membrane Structure and Behavior
- Trace Elements in Health
- Glaucoma and retinal disorders
- Glioma Diagnosis and Treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA regulation and disease
- RNA Interference and Gene Delivery
- Circadian rhythm and melatonin
- Chromatin Remodeling and Cancer
- Advanced Clustering Algorithms Research
- Peroxisome Proliferator-Activated Receptors
- Hedgehog Signaling Pathway Studies
- Caveolin-1 and cellular processes
- Sphingolipid Metabolism and Signaling
The California Eye Institute
2021-2025
Anhui University
2024
University of California, Irvine
2020-2024
Polgenix (United States)
2012-2022
Cleveland Medical Devices
2017-2022
Case Western Reserve University
2005-2018
Louis Stokes Cleveland VA Medical Center
2017
Institute of Molecular Biology and Biophysics
2016
Dr. Reddy's Laboratories (India)
2014
University of Cincinnati
2014
Abstract Objective To report a novel prion disease characterized by distinct histopathological and immunostaining features, associated with an abnormal isoform of the protein (PrP) that, contrary to common diseases, is predominantly sensitive protease digestion. Methods Eleven subjects were investigated at National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, PrP characteristics. Results Patients presented behavioral...
Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting early visual impairment. It therefore crucial to develop a robust therapy that not only compensates for lost function but also protects photoreceptors from further degeneration. Here, we vivo correction an Rpe65 mutation by adenine base editor (ABE) prolongs survival cones mouse model....
Aggregated prion protein (PrPSc), which is detergent-insoluble and partially proteinase K (PK)-resistant, constitutes the major component of infectious prions that cause a group transmissible spongiform encephalopathies in animals humans. PrPSc derives from detergent-soluble PK-sensitive cellular (PrPC) through an α-helix to β-sheet transition. This transition confers on molecule unique physicochemical biological properties, including insolubility nondenaturing detergents, enhanced tendency...
A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding human diseases and lead to therapy development. Here, we applied this strategy identify targets for treatment Stargardt disease, a severe juvenile form macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, crosstalk between GPCR pathways represents an unexplored avenue intervention. We focused receptor family...
Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with nonsyndromic syndromic retinitis pigmentosa. Here, we show absence AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction electroretinogram amplitudes, decreased retinoid content retina, reduced cone opsin expression. Single-cell RNA-Seq results indicate encoded most abundantly...
In daylight, demand for visual chromophore (11-cis-retinal) exceeds supply by the classical cycle. This shortfall is compensated, in part, retinal G-protein-coupled receptor (RGR) photoisomerase, which expressed both pigment epithelium (RPE) and Müller cells. The relative contributions of these two cellular pools RGR to maintenance photoreceptor light responses are not known. Here, we use a cell-specific gene reactivation approach elucidate kinetics RGR-mediated recovery following exposure....
Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies mitigate pathophysiology regardless of the underlying genetic lesion desirable due to diversity mutations found such diseases. We tested a systems pharmacology-based strategy suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, bromocriptine coadministration. The improves cone photoreceptor function...
Emixustat is a visual cycle modulator that has entered clinical trials as treatment for age-related macular degeneration (AMD). This molecule been proposed to inhibit the isomerase RPE65, thereby slowing regeneration of 11-cis-retinal and reducing production retinaldehyde condensation byproducts may be involved in AMD pathology. Previously, we reported all-trans-retinal (atRAL) directly cytotoxic certain primary amine compounds transiently sequester atRAL via Schiff base formation ameliorate...
Photoreceptors rely on distinct membrane compartments to support their specialized function. Unlike protein localization, identification of critical differences in content has not yet been expanded lipids, due the difficulty isolating domain-specific samples. We have overcome this by using SMA coimmunopurify proteins and native lipids from two regions photoreceptor ROS disks. Each sample's copurified were subjected untargeted lipidomic fatty acid analysis. Extensive between center...
Significance Identifying the sequence of events underlying light-induced pathology is important for understanding mechanisms leading to retinal degeneration, and consequently development therapies against diseases. In this study, we characterized early phase degeneration using two-photon microscopy, mass spectroscopy, genetically modified mice. We identified rod photoreceptors as initial locus degeneration. Primary changes included retinoid-dependent formation fluorescent metabolic...
Significance Two-photon excitation (TPE) of retinal fluorophores with infrared light allows monitoring metabolic transformation the retina. TPE imaging can provide information about biochemical events that precede structural damage to retina and thereby accelerate development therapies against blinding diseases. While subcellular endogenous retinoids in pigment epithelium mice nonhuman primates has been achieved, human not fully realized due concerns safety identity molecular signals. We...
Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration (AMD). This study explores effects of AdipoR1 deficiency mice, revealing a striking decline ω3 polyunsaturated fatty acids (PUFA), an increase ω6 FAs, elevated ceramides retina. The impairs peroxisome proliferator-activated α (PPARα) signaling, which is crucial for FA metabolism, particularly affecting proteins transport oxidation retina retinal...
Membrane frizzled-related protein (MFRP), present in the retinal pigment epithelium (RPE), is an integral membrane essential for ocular development and normal physiology of retina. Mutations MFRP are associated with autosomal recessive nonsyndromic nanophthalmos, leading to severe hyperopia early-onset retinitis pigmentosa. While several preclinical gene-augmentation gene-editing trials hold promise future therapies aimed at stopping degeneration restoring function, molecular mechanisms...
Systems pharmacology reveals a combination of GPCR-targeted drugs that prevent retinal degeneration.
Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic environmental perturbations of cellular tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading visual impairment and, in many cases, legal blindness. Despite decades research, therapeutic options for the millions patients suffering these disorders remain severely limited, especially treating...
Abstract Delivering ribonucleoproteins (RNPs) for in vivo genome editing is safer than using viruses encoding Cas9 and its respective guide RNA. However, transient RNP activity does not typically lead to optimal outcomes. Here we show that the efficiency of delivering RNPs can be enhanced by cell-penetrating peptides (covalently fused protein or as excipients) lipid nanoparticles (LNPs) encapsulating optimized stability, delivery potency. Specifically, after screening suitable ionizable...
Investigate whether retinas of mice with impaired retinal cycles exposed to light or kept in the dark tolerate prolonged high-dose administration QLT091001, which contains as an active ingredient, 9-cis-retinal precursor, 9-cis-retinyl acetate.Four- six-week-old Lrat(-/-) and Rpe65(-/-) (n = 126) well crossbred Gnat1(-/-) lacking rod phototransduction 110) were gavaged weekly for 6 months 50 mg/kg either after being bleaching 30 min/wk followed by maintenance a 12-hour ≤ 10 lux)/12-hour...
RPE65 is the essential trans–cis isomerase of classical retinoid (visual) cycle. Mutations in give rise to severe retinal dystrophies, most which are associated with loss protein function and recessive inheritance. The only known exception a c.1430G>A (D477G) mutation that gives dominant retinitis pigmentosa delayed onset choroidal macular involvement. Position 477 distant from functionally critical regions RPE65. Hence, mechanism D477G pathogenicity remains unclear, although misfolding...
The retinal pigment epithelium (RPE) provides vital metabolic support for photoreceptor cells and is an important player in numerous diseases. Gene manipulation mice using the Cre-LoxP system invaluable tool studying genetic basis of these However, existing RPE-targeted Cre mouse lines have critical limitations that restrict their reliability studies disease pathogenesis treatment, including mosaic expression, inducer-independent activity, off-target intrinsic toxicity. Here, we report...
Chronic wasting disease (CWD), a transmissible prion that affects elk and deer, poses new challenges to animal human health. Although the transmission of CWD humans has not been proven, it remains possibility. If this were occur, is important know whether "acquired" would show phenotype including scrapie protein (PrP(Sc)) features differ from those associated with sporadic disease. In study, we have compared pathological profiles PrP(Sc) characteristics in brains CWD-affected deer subjects...
Age-related macular degeneration (AMD) is a neurodegenerative disease that causes adult-onset blindness. There are 2 forms of this progressive disease: wet and dry. Currently there no cure for AMD, but several treatment options have started to emerge making early detection critical therapeutic success. Analysis the eyes Abca4-/-Rdh8-/- mice display light-induced retinal indicates 11-cis-retinal docosahexaenoic acid (DHA) levels were significantly decreased as compared with control...
Noninvasive imaging of visual system components in vivo is critical for understanding the causal mechanisms retinal diseases and developing therapies their treatment. However, ultraviolet light needed to excite endogenous fluorophores that participate metabolic processes retina highly attenuated by anterior segment human eye. In contrast, 2-photon excitation fluorescence with pulsed infrared overcomes this obstacle. Reducing exposure laser radiation remains a major barrier advancing...