A5012517507- Retinal Development and Disorders
- Photoreceptor and optogenetics research
- Genetic and Kidney Cyst Diseases
- Retinal Diseases and Treatments
- Cellular transport and secretion
- Neurobiology and Insect Physiology Research
- Bacterial Genetics and Biotechnology
- CRISPR and Genetic Engineering
- Renal and related cancers
- bioluminescence and chemiluminescence research
- Developmental Biology and Gene Regulation
- Microtubule and mitosis dynamics
- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- Retinoids in leukemia and cellular processes
- Receptor Mechanisms and Signaling
- Animal Genetics and Reproduction
- Bacteriophages and microbial interactions
- Phosphodiesterase function and regulation
- Escherichia coli research studies
- Hedgehog Signaling Pathway Studies
- Photochromic and Fluorescence Chemistry
- Genetic Syndromes and Imprinting
- Retinopathy of Prematurity Studies
- Photosynthetic Processes and Mechanisms
West Virginia University
2015-2025
Morgantown High School
2012-2022
Blanchette Rockefeller Neurosciences Institute
2017-2020
Laboratoire de Biochimie
2018
Ophthalmology Associates (United States)
2016
Center for Neurosciences
2009-2014
Health Center
2008
University of Washington
1999-2007
Seattle University
2007
University College Dublin
2004
Leber congenital amaurosis (LCA4) has been linked to mutations in the photoreceptor-specific gene Aryl hydrocarbon interacting protein like 1 (Aipl1). To investigate essential role of AIPL1 retina, we generated a mouse model LCA by inactivating Aipl1 gene. In Aipl1(-/-) retinas, outer nuclear layer develops normally, but rods and cones then quickly degenerate. mice have highly disorganized, short, fragmented photoreceptor segments lack both rod cone electroretinogram responses. Recent...
Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the "Warburg Effect"), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the photoreceptors does get oxidized their mitochondria required for visual function, photoreceptor structure and viability, normal neuron-glial interaction, homeostasis retinal metabolism. The mitochondrial carrier (MPC) links Retina-specific deletion MPC1 results progressive...
Alternative pre-mRNA splicing expands the coding capacity of eukaryotic genomes, potentially enabling a limited number genes to govern development complex anatomical structures. is particularly prevalent in vertebrate nervous system, where it required for neuronal and function. Here, we show that photoreceptor cells, type sensory neuron, express characteristic program affects broad set transcripts initiated prior light sensing outer segments. Surprisingly, photoreceptors lack prototypical...
Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by developmental abnormalities and vision loss. To date, mutations in 21 genes have been linked to BBS. The products of eight these BBS form a stable octameric complex termed the BBSome. Mutations BBS8, component BBSome, cause early loss, but role BBS8 supporting not known. understand mechanisms which supports rod cone photoreceptor function, we generated animal models lacking BBS8. loss protein led concomitant...
SecA insertion and integration into theEscherichia coli inner membrane is a critical step for the catalysis of protein translocation across this layer. To understand further, topology was investigated. determine which regions are periplasmically exposed, right-side out vesicles were prepared from strains synthesizing monocysteine variants produced by mutagenesis probed with membrane-impermeant sulfhydryl-labeling reagent. contain membrane-integration determinants, inverted subjected to...
Leber congenital amaurosis (LCA) caused by mutations in Aryl hydrocarbon receptor interacting protein like-1 ( Aipl1) is a severe form of childhood blindness. At 4 weeks age, mouse model LCA lacking AIPL1 exhibits complete degeneration both rod and cone photoreceptors. Rod cell death occurs due to rapid destabilization phosphodiesterase, an enzyme essential for survival function. However, little understood regarding the role Cone observed absence could be indirect 'bystander effect'...
The small GTPase, ADP-ribosylation factor-like 3 (ARL3), has been proposed to participate in the transport of proteins photoreceptor cells. Moreover, it implicated pathogenesis associated with X-linked retinitis pigmentosa (XLRP) resulting from mutations ARL3 GTPase activating protein, 2 (RP2). To determine importance rod cells, we generated transgenic mice expressing a dominant active form (ARL3-Q71L) under rod-specific promoter. ARL3-Q71L animals exhibited extensive cell death after...
Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a photoreceptor-specific chaperone that stabilizes the effector enzyme of phototransduction, cGMP phosphodiesterase 6 (PDE6). Mutations in AIPL1 gene cause severe inherited retinal dystrophy, Leber congenital amaurosis type 4 (LCA4), manifests as loss vision during first year life. In this study, we generated three-dimensional (3D) organoids (ROs) from human induced pluripotent stem cells (hiPSCs) derived an LCA4 patient...
Mutations in the photoreceptor membrane guanylyl cyclase RetGC-1 have been linked to autosomal dominant cone–rod dystrophy. Three mutations were identified that alter strictly conserved residues within dimerization domain, a region predicted form an amphipathic α-helical coil. Here we report on biochemical characterization of one mutations, substitution cysteine for arginine at residue 838. We generated this mutation vitro and measured its catalytic activity sensitivity activating protein 1...
RetGC-1, a member of the membrane guanylyl cyclase family proteins, is regulated in photoreceptor cells by Ca(2+)-binding protein known as GCAP-1. Proper regulation RetGC-1 essential for normal light adaptation and recovery to dark state. In this study we show that cGMP synthesis requires dimerization, because critical functions catalytic site must be provided each two polypeptide chains dimer. We also an intact alpha-helical coiled-coil structure required provide dimerization strength...
The most common form of blindness at birth, Leber's congenital amaurosis (LCA), is inherited in an autosomal recessive fashion. Mutations six different retina-specific genes, including a recently discovered gene, AIPL1, have been linked to LCA humans. To understand the molecular basis caused by aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) mutations, and elucidate normal function we performed yeast two-hybrid screen using AIPL1 as bait. demonstrated that interacts specifically...
Bardet-Biedl syndrome (BBS) is a genetic disorder affecting multiple systems and organs in the body. Several mutations genes associated with BBS affect only photoreceptor cells cause nonsyndromic retinitis pigmentosa (RP), raising issue of why certain manifest as systemic whereas other changes same gene specific cell type. Here, we show that cell-type-specific alternative splicing responsible for confining phenotype A-to-G substitution 3' splice site BBS8 exon 2A (IVS1-2A>G mutation) to...
Mutations in the Joubert syndrome-associated small GTPase ARL13B are linked to photoreceptor impairment and vision loss. To determine role of development, function, maintenance ciliated photoreceptors, we generated a pan-retina knock-out (Six3-Cre) rod photoreceptor-specific inducible conditional (Pde6g-CreERT2) using murine models. Embryonic deletion led defects retinal development with reduced cell proliferation. In absence ARL13B, photoreceptors failed develop outer segment (OS)...
Retinitis pigmentosa (RP) is a debilitating blinding disease affecting over 1.5 million people worldwide, but the mechanisms underlying this are not well understood. One of common models used to study RP retinal degeneration-10 (rd10) mouse, which has mutation in Phosphodiesterase-6b (Pde6b) that causes phenotype mimicking human disease. In rd10 mice, photoreceptor cell death occurs with exposure normal light conditions, as demonstrated study, rearing these mice dark preserves their...
Abstract The Musashi proteins, MSI1 and MSI2, are conserved RNA binding proteins with a role in the maintenance renewal of stem cells. Contrasting this role, terminally differentiated photoreceptor cells express high levels pointing to for two vision. Combined knockout Msi1 Msi2 mature abrogated retinal response light caused cell death. In perform distinct nuclear cytoplasmic functions. nucleus, promote splicing photoreceptor-specific alternative exons. Surprisingly, exons genes critical...
Abstract Mutations in Cytosolic Carboxypeptidase-like Protein 5 (CCP5) are associated with vision loss humans. To decipher the mechanisms behind CCP5-associated blindness, we generated a novel mouse model lacking CCP5. In this model, found that increased tubulin glutamylation led to progressive cone-rod dystrophy, cones showing more pronounced and earlier functional than rod photoreceptors. The observed reduction was not due cell death, levels, or mislocalization of major phototransduction...
To design and validate a cost-effective titratable system capable of light-induced photoreceptor dysfunction damage in pigmented mice. Two commonly used mouse strains vision research, C57BL/6J 129SVE mice, were exposed individually to varying light intensities custom-designed boxes. Visual function was assessed by ERG, which conducted two days prior, one day, week after exposure. For morphological evaluation health, we stained retinal sections with hematoxylin eosin followed microscopy....
SecA ATPase promotes Escherichia coli protein translocation by its association with the preprotein or preprotein-SecB complex, anionic phospholipids, and other core component of translocase, integral membrane SecYEG. Using ligand affinity blotting we demonstrate a direct interaction SecY protein. Proteolysis gene truncation fusion studies were used to further define this interaction. Our results that carboxyl-terminal third binds amino-terminal 107 amino acid residues The demonstration these...
Prenylation is the posttranslational modification of a carboxyl-terminal cysteine residue proteins that terminate with CAAX motif. Following prenylation, last three amino acids are cleaved off by endoprotease, RAS-converting enzyme 1 (RCE1), and prenylcysteine methylated. Although it clear prenylation increases membrane affinity proteins, less known about importance postprenylation processing steps. RCE1 function has been studied in variety tissues but not neuronal cells. To approach this...
In rod photoreceptors, several phototransduction components display light-dependent translocation between cellular compartments. Notably, the G protein transducin translocates from outer segments to inner segments/spherules in bright light, but functional consequences of remain unclear. We generated transgenic mice where light-induced is impaired. These exhibited slow photoreceptor degeneration, which was prevented if they were dark-reared. Physiological recordings showed that control and...
Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects characterized at most severe end of LCA spectrum. The rapid photoreceptor loss observed patient population mimicked mouse model lacking AIPL1. Using this model, we evaluated if replacement therapy using recent advancements...
Photoreceptor neurons are surrounded by an extracellular matrix, called the interphotoreceptor matrix (IPM). Activities crucial to vision occur within IPM, including trafficking of nutrients and metabolites, retinal attachment, interactions needed for normal outer segment phagocytosis. The IPM includes following two unique proteoglycans: proteoglycan 1 (IMPG1) IMPG2. Patients with mutations in IMPG1/IMPG2 develop visual deficits subretinal material accumulation, highlighting critical role...