A5036106868- Retinal Development and Disorders
- Photoreceptor and optogenetics research
- Receptor Mechanisms and Signaling
- Genetic and Kidney Cyst Diseases
- Glaucoma and retinal disorders
- Mitochondrial Function and Pathology
- Retinal Diseases and Treatments
- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Molecular Communication and Nanonetworks
- bioluminescence and chemiluminescence research
- Circadian rhythm and melatonin
- Neuroscience and Neuropharmacology Research
- Advanced Fluorescence Microscopy Techniques
- Photosynthetic Processes and Mechanisms
- Neurobiology and Insect Physiology Research
- Adenosine and Purinergic Signaling
- Endoplasmic Reticulum Stress and Disease
- Cellular Mechanics and Interactions
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA regulation and disease
- CRISPR and Genetic Engineering
- Biotin and Related Studies
- Biomedical Research and Pathophysiology
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
University of Alabama at Birmingham
2016-2025
Civitan International
2018
Institute of Neurobiology
2014
Allen Institute for Brain Science
2014
University of Alabama
2008
Baylor College of Medicine
2004-2006
University of Houston
2004
Philipps University of Marburg
2004
Brandeis University
2003
G protein-coupled receptor (GPCR) activation mediated by ligand-induced structural reorganization of its helices is poorly understood. To determine the universal elements this conformational switch, we used evolutionary tracing (ET) to identify residue positions commonly important in diverse GPCRs. When mapped onto rhodopsin structure, these trace residues cluster into a network contacts from retinal binding site protein-coupling loops. Their roles generic transduction mechanism were...
Abstract As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs shed and remade daily. Defects in this process, due mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, mechanism...
Recent studies on the endoplasmic reticulum stress have shown that unfolded protein response (UPR) is involved in pathogenesis of inherited retinal degeneration caused by mutant rhodopsin. However, main question whether UPR activation actually triggers remains to be addressed. Thus, this study, we created a mouse model for persistently activated assess physiological and morphological parameters associated with disease state highlight potential mechanism which can promote degeneration. We...
This report describes the biochemical characterization of a double mutant rhodopsin (N2C,D282C) in which Cys residues engineered into protein at positions 2 (in amino-terminal extracellular domain) and 282 loop between transmembrane helices 6 7) are shown to form disulfide bond increase thermal stability unliganded or opsin protein. Wild-type does not survive detergent solubilization purification pH 7.5 25 °C. In contrast, N2C,D282C survives protocol loses less than 50% activity after...
Mutations in the rhodopsin gene cause approximately one-tenth of retinitis pigmentosa cases worldwide, and most result endoplasmic reticulum retention apoptosis. Other mutations receptor mislocalization, diminished/constitutive activity, or faulty protein-protein interactions. The purpose this study was to test for mechanisms by which autosomal dominant mutation Ter349Glu causes an early, rapid retinal degeneration patients. adds additional 51 amino acids C terminus protein. Folding ligand...
purpose. Mutations in RHO, PDE6B, and GNAT1 can lead to autosomal dominant congenital stationary night blindness (adCSNB). The study was conducted identify the genetic defect a large Swiss family affected with adCSNB investigate pathogenic mechanism of mutation. methods. Two cousins were examined clinically by standard methods: funduscopy, EOG, ERG, dark adaptometry. Twelve members screened for mutations RHO. ability mutant rhodopsin activate transducin constitutively monitored measuring...
The Thr94 → Ile mutation in the second transmembrane segment of rhodopsin has been reported to be associated with a congenital night blindness phenotype large Irish pedigree. Previously, two other known mutants that cause blindness, A292E and G90D, have shown vitro constitutively activate G protein transducin absence chromophore. proposed mechanism constitutive activation these is an electrostatic disruption active site salt bridge between Glu113 Lys296 contributes stabilization inactive...
Mutations in the Rhodopsin (Rho) gene can lead to autosomal dominant retinitis pigmentosa (RP) humans. Transgenic mouse models with mutations Rho have been developed study disease. However, it is difficult know source of photoreceptor (PR) degeneration these transgenic because overexpression wild type (WT) alone PR degeneration. Here, we report two chemically mutagenized carrying point (Tvrm1 an Y102H mutation and Tvrm4 I307N mutation). Both mutants express normal levels rhodopsin that...
To determine whether the age-regulating protein klotho was expressed in retina and absence of affected retinal function.Immunohistochemistry qPCR knockout wild-type mice were used to detect expression retina. Immunohistochemistry probe for differences proteins important synaptic function, structure, ionic flux. Electroretinography (ERG) conducted on animals across lifespan decreased affects function.Klotho mRNA detected mouse retina, with present all nuclear layers. Over short (∼8 weeks), no...
Tyrosinase is a key enzyme in melanin biosynthesis. Mutations the gene encoding tyrosinase (Tyr) cause oculocutaneous albinism (OCA1) humans. Alleles of Tyr have been useful studying pigment biology and coat color formation. Over 100 different alleles reported mice, which ≈24% are spontaneous mutations, ≈60% radiation-induced, remaining were obtained by chemical mutagenesis targeting. Therefore, most mutations random could not be predicted priori. Using CRISPR-Cas9 system, we targeted two...
Purpose: To identify the role of BBSome protein Bardet–Biedl syndrome 5 (BBS5) in photoreceptor function, trafficking, and structure using a congenital mutant mouse model. Methods: Bbs5–/– mice (2 9 months old) were used to assess retinal function morphology. Hematoxylin eosin staining sections was performed visualize histology. Electroretinography analyze rod cone function. Retinal localization visualized immunofluorescence (IF) within cryosections. TUNEL quantify cell death. Transmission...
ABSTRACT The transition zone (TZ) is a domain at the base of cilium that involved in maintaining ciliary compartment‐specific sensory and signaling activity by regulating cilia protein composition. Mutations TZ proteins result dysfunction, often causing pleiotropic effects observed group human diseases classified as ciliopathies. purpose this study to describe importance component Meckel‐Grüber syndrome 6 ( Mks6 ) several organ systems tissues regarding ciliogenesis maintenance using...
In an examination of the effect three rhodopsin night blindness mutations on rate association 11-cis-retinal with opsin, one (G90D) was found to slow reaction by more than 80-fold. This does not appear be general as two other mutants (A292E and T94I) were bind retinal slowed kinetics. However, T94D similar G90D in that binding dramatically slowed. Gly90 Thr94 are both located active site protein close Schiff base counterion Glu113. Thus, kinetics formation correlate introduction a negative...
Precise vectorial transport of rhodopsin is essential for rod photoreceptor health and function. Mutations that truncate or extend the C terminus disrupt this transport, lead to retinal degeneration blindness in human patients mouse models. Here we show such mutations binding small GTPase rab11a. The rhodopsin–rab11a interaction a direct does not depend on nucleotide state Expression EGFP-rab11a fusion proteins Xenopus laevis photoreceptors revealed status rab11a affects its subcellular...
Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for and those exist work only recessively inherited forms. To better understand pathogenesis RP, multiple mouse models have been generated bearing mutations found human patients including Q344X rhodopsin knock-in mouse. In recent years, immune system was shown to play an increasingly important role RP degeneration. By way electroretinography, optical...
For sensitive detection of rare gene repair events in terminally differentiated photoreceptors, we generated a knockin mouse model by replacing one rhodopsin allele with form the human that causes severe, early-onset retinitis pigmentosa. The contains premature stop codon at position 344 (Q344X), cDNA encoding enhanced green fluorescent protein (EGFP) its 3′ end, and modified 5′ untranslated region to reduce translation rate so mutant does not induce retinal degeneration. Mutations eliminate...
Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate progression, and treatments. While RDs caused by a plethora different mutations, all result the same outcome blindness. treatments, both gene therapy-based drug-based, have been developed to slow or halt disease progression prevent further blindness, only small handful forms treatments available, which primarily for recessively inherited forms. Using immunohistochemical methods...