A5047985485- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Photoreceptor and optogenetics research
- Neuroscience and Neuropharmacology Research
- Advanced Glycation End Products research
- Adipose Tissue and Metabolism
- bioluminescence and chemiluminescence research
- Melanoma and MAPK Pathways
- Receptor Mechanisms and Signaling
- Glaucoma and retinal disorders
- Circadian rhythm and melatonin
- Mechanisms of cancer metastasis
- Pancreatic function and diabetes
- Retinoids in leukemia and cellular processes
- Aldose Reductase and Taurine
- Cellular transport and secretion
- Intraocular Surgery and Lenses
- Mitochondrial Function and Pathology
- Photochromic and Fluorescence Chemistry
- Neuroscience and Neural Engineering
- Anesthesia and Sedative Agents
- Retinopathy of Prematurity Studies
- Nuclear Receptors and Signaling
- Light effects on plants
- ATP Synthase and ATPases Research
Louis Stokes Cleveland VA Medical Center
2015-2025
Cleveland Eye Clinic
2016-2025
VA Northeast Ohio Healthcare System
2020-2025
Cleveland Clinic
2015-2024
United States Department of Veterans Affairs
2016-2019
University School
2009
Case Western Reserve University
2006-2009
National Institute of Neurological Disorders and Stroke
2002
National Institutes of Health
2002
Zero to Three
2002
The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling intermediates; however, little is known about their isoform-specific functions <i>in vivo</i>. We have examined the role of in neural development by conditional inactivation murine <i>mapk1/</i>ERK2 gene progenitor cells developing cortex. ERK MAP kinase (MAPK) activity required for neuronal cell fate determination. Loss resulted a reduction cortical thickness attributable to impaired proliferation...
Disrupted ERK1/2 (MAPK3/MAPK1) MAPK signaling has been associated with several developmental syndromes in humans; however, mutations ERK1 or ERK2 have not described. We demonstrate haplo-insufficient expression patients a novel approximately 1 Mb micro-deletion distal 22q11.2, region that includes ERK2. These exhibit conotruncal and craniofacial anomalies arise from perturbation of neural crest development defects comparable to the DiGeorge syndrome spectrum. Remarkably, these are replicated...
The retina is one of the most metabolically active tissues in body and utilizes glucose to produce energy intermediates required for daily renewal photoreceptor cell outer segments. Glucose transporter 1 (GLUT1) facilitates transport across blood retinal barrier (BRB) formed by pigment epithelium (RPE) inner BRB endothelium. We used conditional knockout mice study impact reducing RPE on Müller glial cells. Transgenic expressing Cre recombinase under control Bestrophin1 ( Best1) promoter were...
In the diabetic retina, cellular changes in retinal pigment epithelium (RPE) and neurons occur before vision loss or retinopathy can be identified clinically. The precise etiologies of pathology are poorly defined, it remains unclear if onset progression dysfunction differ between type 1 2 diabetes. Three mouse models were used to compare time course RPE involvement C57BL/6J mice injected with streptozotocin (STZ mice) modeled diabetes, whereas Lepr db/db on both BKS B6.BKS background...
Parallel visual pathways are initiated at the first retinal synapse by signaling between rod and cone photoreceptors two general classes of bipolar cells. For normal function, ON or depolarizing cells (DBCs) require G-protein-coupled receptor, mGluR6, an intact cascade transient receptor potential melastatin 1 (TRPM1) cation channel. In addition, another seven transmembrane protein, GPR179, is required for DBC function recruits regulators G-protein (RGS) proteins, RGS7 RGS11, to dendritic...
Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular circadian activity within cone reveal a role clock genes Bmal1 Per2 in regulating spectral identity. ChIP analysis revealed that BMAL1 binds promoter region thyroid hormone (TH)-activating enzyme type 2 iodothyronine deiodinase (Dio2) thus regulates expression Dio2. TH treatment...
In the vertebrate retina, neuronal circuitry required for visual perception is organized within specific laminae. Photoreceptors convey external information to bipolar and horizontal cells at triad ribbon synapses established outer plexiform layer (OPL), initiating retinal processing. However, molecular mechanisms that organize these three classes of processes OPL, thereby ensuring appropriate synapse formation, remain largely unknown. Here we show mice with null mutations in Sema6A or...
Purpose: Loss of photoreceptor cells is associated with retinal vascular degeneration in retinitis pigmentosa, whereas the presence implicated diabetic retinopathy. To investigate how both absence and photoreceptors could damage vasculature, we compared two mouse models (opsin−/− RhoP23H/P23H ) control C57Bl/5J mice, each without diabetes. Methods: Retinal thickness, superoxide, expression inflammatory proteins, ERG optokinetic responses, leukocyte cytotoxicity, capillary were evaluated at 1...
Purpose: Recent evidence suggests that retinal photoreceptor cells have an important role in the pathogenesis of microvascular lesions diabetes. We investigated rod cell phototransduction on early diabetic retinopathy (DR) using Gnat1−/− mice (which causes permanent inhibition without degeneration). Methods: Retinal thickness, oxidative stress, expression inflammatory proteins, electroretinograms (ERG) and optokinetic responses, capillary permeability degeneration were evaluated at up to 8...
Photoreceptors consume glucose supplied by the choriocapillaris to support phototransduction and outer segment (OS) renewal. Reduced supply underlies photoreceptor cell death in inherited retinal degeneration age-related disease. We have previously shown that restricting transport into retina conditional deletion of Slc2a1 encoding GLUT1 resulted loss impaired OS However, neurons, glia, pigment epithelium play specialized, synergistic roles metabolite exchange, cell-specific map uptake...
In this study we develop and use a gain-of-function mouse allele of the Down syndrome cell adhesion molecule ( Dscam ) to complement loss-of-function models. We assay role in promoting death, spacing, laminar targeting neurons developing retina. find that ectopic or overexpression is sufficient drive death. Gain-of-function studies indicate not increase spatial organization, prevent cell-to-cell pairing, promote active avoidance retina, despite similarity phenotype retina phenotypes observed...
The bone morphogenetic proteins (BMPs) play an inductive role in the generation of cerebellar granule cells embryonically. Therefore, we chose to look at their effects on cell survival and differentiation postnatally. express mRNA for both BMP-6 BMP-7, as well receptors BMPRIA BMPRII, demonstrating that postnatal have ability form heterodimer needed respond BMPs. BMP-7 promotes survival, with a maximal effect 10 ng/ml, whereas tenfold more is needed: Both were active over course 8 days...
Chronic inflammation and oxidative stress are critical components in the pathogenic cascade of early diabetic retinopathy, characterized by neuronal vascular degeneration. We investigated pharmacologic inhibition proinflammatory leukotriene for therapeutic benefit retinopathy. Using streptozotocin-induced diabetes mouse model, we administered montelukast, a receptor antagonist, diabetes-related retinal pathology was assessed. Early biochemical cellular function measures were evaluated at 3...
Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization glucose levels delays its progression. In hyperglycemia, hexokinase saturated and excess metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies reduce retinal accumulation prevention DR have been elusive because low dehydrogenase in retina inadequate inhibition reductase. Using systemic conditional genetic...
ABSTRACT Type 2 diabetes affects more than 30 million people in the US, and a major complication is kidney disease. During analysis of lipotoxicity diabetic disease, global fatty acid transport protein-2 (FATP2) gene deletion was noted to markedly reduce plasma glucose db/db mice due sustained insulin secretion. To identify mechanism, we observed that islet FATP2 expression restricted α-cells, α-cell functional. Direct evidence FATP2KO-induced α-cell-mediated GLP-1 secretion included...
Mutations in genes expressed the retinal pigment epithelium (RPE) underlie a number of human inherited disorders that manifest with photoreceptor degeneration. Because light-evoked responses RPE are generated secondary to rod activity, response reductions observed patients or animal models may simply reflect decreased input. The purpose this study was define how electrophysiological characteristics change when complement photoreceptors is decreased. To measure function, we used an...
Abstract Atypical protein kinase Cs zeta and lambda/iota play a functional role in the regulation of NGF‐induced differentiation survival pheochromocytoma, PC12 cells [Coleman Wooten, 1994 ; Wooten et al., 1999 ]. Here we demonstrate an NGF‐dependent interaction aPKC with its binding protein, ZIP/p62. Although, ZIP/p62 was not PKC‐ι substrate, formation ZIP/p62‐aPKC complex by NGF occurred post activation regulated tyrosine phosphorylation state aPKC. Furthermore, localization observed...
Abstract Streptozotocin (STZ)-induced diabetes is associated with reductions in the electrical response of outer retina and retinal pigment epithelium (RPE) to light. Aldose reductase (AR) first enzyme required polyol-mediated metabolism glucose, AR inhibitors have been shown improve diabetes-induced electroretinogram (ERG) defects. Here, we used control −/− mice determine if genetic inactivation this likewise inhibits electrophysiological defects observed a mouse model type 1 diabetes. STZ...
The electroretinogram c-wave is generated by the summation of positive polarity hyperpolarization apical RPE membrane and a negative slow PIII response Müller glia cells. Therefore, reduction noted in prior studies mouse models diabetes could reflect component or an increase PIII. present study used genetic approach to distinguish between these two alternatives.Nyxnob mice lack ERG b-wave, revealing early phase To visualize changes due diabetes, Nyxnob were given streptozotocin (STZ)...