A5035197614- Retinal Development and Disorders
- Photoreceptor and optogenetics research
- Retinal Diseases and Treatments
- Mitochondrial Function and Pathology
- RNA regulation and disease
- CRISPR and Genetic Engineering
- Herpesvirus Infections and Treatments
- Toxin Mechanisms and Immunotoxins
- Epigenetics and DNA Methylation
- Neurobiology and Insect Physiology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Advanced Fluorescence Microscopy Techniques
- Neuroscience and Neuropharmacology Research
- bioluminescence and chemiluminescence research
- Cellular transport and secretion
- Retinopathy of Prematurity Studies
- Advanced Glycation End Products research
- interferon and immune responses
- Morinda citrifolia extract uses
- Alzheimer's disease research and treatments
- Microtubule and mitosis dynamics
- Circular RNAs in diseases
- Receptor Mechanisms and Signaling
- Single-cell and spatial transcriptomics
- Photosynthetic Processes and Mechanisms
National Institutes of Health
2011-2025
National Eye Institute
2011-2025
National Cancer Institute
2012
UConn Health
2007-2011
Center for Infectious Disease Research
1996
Purpose: Cell death in neurodegeneration occurs at the convergence of diverse metabolic pathways. In retina, a common underlying mechanism involves mitochondrial dysfunction since photoreceptor homeostasis and survival are highly susceptible to altered aerobic energy metabolism. We sought develop an assay directly measure oxygen consumption intact retina with goal identifying alterations respiration during degeneration. Methods: Circular punches freshly isolated mouse adjacent optic nerve...
Dysfunction or death of photoreceptors is the primary cause vision loss in retinal and macular degenerative diseases. As have an intimate relationship with pigment epithelium (RPE) for exchange macromolecules, removal shed membrane discs retinoid recycling, improved understanding development photoreceptor-RPE complex will allow better design gene- cell-based therapies. To explore epigenetic contribution to we generated conditional knockout alleles DNA methyltransferase 1 (Dnmt1) mice....
Abstract Retinal diseases exhibit extensive genetic heterogeneity and complex etiology with varying onset severity. Mutations in over 200 genes can lead to photoreceptor dysfunction and/or cell death retinal neurodegeneration. To deduce molecular pathways that initiate drive death, we adopted a temporal multiomics approach examined cellular events newborn developing photoreceptors before the of degeneration widely-used Pde6brd1/rd1 (rd1) mouse, model autosomal recessive retinitis pigmentosa...
Animal models of human disease are an invaluable component studies aimed at understanding pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) most common cause X-linked (XLRP) estimated to 20% all retinal dystrophy cases. A majority RPGR mutations present ORF15, purine-rich terminal exon predominant splice-variant expressed retina. Here we describe genetic phenotypic characterization degeneration 9 (Rd9) strain mice, a...
RNA-binding proteins (RBPs) perform diverse functions including the regulation of chromatin dynamics and coupling transcription with RNA processing. However, our understanding their actions in mammalian neurons remains limited. Using affinity purification, yeast-two-hybrid proximity ligation assays, we identified interactions multiple RBPs NRL, a Maf-family bZIP factor critical for retinal rod photoreceptor development function. In addition to splicing, many NRL-interacting are associated...
RNA-binding proteins (RBPs) perform diverse functions including the regulation of chromatin dynamics and coupling transcription with RNA processing. However, our understanding their actions in mammalian neurons remains limited. Using affinity purification, yeast-two-hybrid proximity ligation assays, we identified interactions multiple RBPs neural retina leucine (NRL) zipper, a Maf-family factor critical for retinal rod photoreceptor development function. In addition to splicing, many...
Transcripts from many mitochondrial genes in kinetoplastids undergo RNA editing, a posttranscriptional process which inserts and deletes uridines. By assaying for deletion editing vitro, we found that the activity Trypanosoma brucei lysates (S.D. Seiwert K.D. Stuart), Science 266:114-117,1994) sediments with peak of approximately 20S. helicase, terminal uridylyl transferase, ligase, adenylation activities, may have role cosediment broad distribution, most each at 35 to 40S. Most ATPase 6...
Phototransduction machinery in vertebrate photoreceptors is contained within the membrane discs of outer segments. Daily renewal 10% photoreceptor segments requires stringent control gene expression. Rhodopsin constitutes over 90% protein rod discs, and its altered expression or transport associated with dysfunction and/or death. Two cis-regulatory sequences have been identified upstream rhodopsin transcription start site. While proximal promoter binds to specific factors, including NRL CRX,...
Purpose: To test the hypothesis that mitochondrial respiration contributes to local changes in hydration involved phototransduction-driven expansion of outer retina, as measured by structural responses on optical coherence tomography (OCT) and diffusion magnetic resonance imaging (MRI). Methods: Oxygen consumption rate reserve capacity freshly isolated C57BL/6 129S6/SvEvTac mouse retina were using a Seahorse Extracellular Flux Analyzer. Light-stimulated layer water content was determined...
Aging-associated functional decline is accompanied by alterations in the epigenome. To explore DNA modifications that could influence visual function with age, we perform whole-genome bisulfite sequencing of purified mouse rod photoreceptors at four ages and identify 2,054 differentially methylated regions (DMRs). We detect many DMRs during early stages aging regulatory regions, some these cluster chromosomal hotspots, especially on chromosome 10, which includes a longevity interactome....
Development of rod photoreceptors in the mammalian retina is critically dependent on basic motif-leucine zipper transcription factor NRL (neural leucine zipper). In absence NRL, photoreceptor precursors mouse produce only cones that primarily express S-opsin. Conversely, ectopic expression post-mitotic leads to a rod-only retina. To explore role signaling molecules modulating function, we identified putative sites post-translational modification protein by silico analysis. Here, demonstrate...
In retinal photoreceptors, vectorial transport of cargo is critical for transduction visual signals, and defects in intracellular trafficking can lead to photoreceptor degeneration vision impairment. Molecular signatures associated with routing vesicles photoreceptors are poorly understood. We previously reported the identification a novel rod specific isoform Receptor Expression Enhancing Protein (REEP) 6, which belongs family proteins involved receptors plasma membrane. Here we show that...
The herpes simplex virus 1 (HSV-1) UL6 portal protein forms a 12-subunit ring structure at unique capsid vertex which functions as conduit for the encapsidation of viral genome. We have demonstrated previously that leucine zipper region is important intersubunit interactions and stable formation (J. K. Nellissery, R. Szczepaniak, C. Lamberti, S. Weller, J. Virol. 81:8868-8877, 2007). now demonstrate disulfide bonds exist between monomeric subunits contribute to and/or stability. Intersubunit...
The herpes simplex virus type 1 UL6 protein forms a 12-subunit ring structure at unique capsid vertex which functions as conduit for encapsidation of the viral genome. To characterize domains that are involved in intersubunit interactions and with other proteins, we engineered set deletion mutants spanning entire gene. Three constructs, D-5 (Delta 198-295), D-6 322-416), D-LZ 409-473, putative leucine zipper was removed), were introduced into All three mutant viruses produced only B capsids,...
Disulfide bonds reportedly stabilize the capsids of several viruses, including papillomavirus, polyomavirus, and simian virus 40, have been detected in herpes simplex (HSV) capsids. In this study, we show that mature HSV-1 virions, capsid proteins VP5, VP23, VP19C, UL17, UL25 participate covalent cross-links, these are susceptible to dithiothreitol (DTT). addition, tegument were found high-molecular-weight complexes, VP22, UL36, UL37. Cross-linked complexes can be virions isolated presence...
Functional complexity of the eukaryotic mitochondrial proteome is augmented by independent gene acquisition from bacteria since its endosymbiotic origins. Mammalian homologs many ancestral proteins have uncharacterized catalytic activities. Recent forward genetic approaches attributed functions to in established metabolic pathways, thereby limiting possibility identifying novel biology relevant human disease. We undertook a bottom-up biochemistry approach discern evolutionarily conserved...
Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding RabGEF1 or Rabex-5) only gene with Rab GTPases that exhibited strong concordance retinal photoreceptor differentiation. Loss in mice (Rabgef1-/-) resulted defects specifically morphology almost complete...
Abstract Trafficking of transducin (Gα t ) in rod photoreceptors is critical for adaptive and modulatory responses the retina to varying light intensities. In addition fine-tuning phototransduction gain outer segments (OSs), light-induced translocation Gα synapse enhances bipolar synaptic transmission. Here, we show that rod-specific loss Frmpd1 (FERM PDZ domain containing 1), both female male mice, results delayed return from back dark, compromising capacity rods recover adaptation....
Maf-family basic motif leucine zipper protein NRL specifies rod photoreceptor cell fate during retinal development and, in concert with homeodomain CRX and other regulatory factors, controls the expression of most rod-expressed genes including visual pigment gene Rhodopsin (Rho). Transcriptional activity is modulated by post-translational modifications, especially phosphorylation, mutations at specific phosphosites can lead to degeneration. During our studies elucidate NRL-mediated...
Post-translational modifications such as phosphorylation, nitrosylation, and pupylation modulate multiple cellular processes in Mycobacterium tuberculosis. While protein methylation at lysine arginine residues is widespread eukaryotes, to date only two methylated proteins Mtb have been identified. Here, we report the identification of and/or nine mycobacterial proteins. Among identified, chose MtrA, an essential response regulator a two-component signaling system, which gets on examine...
Abstract RNA-binding proteins (RBPs) perform diverse functions including the regulation of chromatin dynamics and coupling transcription with RNA processing. However, our understanding their actions in mammalian neurons remains limited. Using affinity purification, yeast-two-hybrid proximity ligation assays, we identified interactions multiple RBPs NRL, a Maf-family bZIP factor critical for retinal rod photoreceptor development function. In addition to splicing, many NRL-interacting are...