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1.
Proc Natl Acad Sci U S A ; 119(28): e2202256119, 2022 07 12.
Article in English | MEDLINE | ID: mdl-35867766

ABSTRACT

Phenotypic variations in the retinal pigment epithelial (RPE) layer are often a predecessor and driver of ocular degenerative diseases, such as age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We previously identified the orphan nuclear receptor-related 1 (NURR1), from a nuclear receptor atlas of human RPE cells, as a candidate transcription factor potentially involved in AMD development and progression. In the present study we characterized the expression of NURR1 as a function of age in RPE cells harvested from human donor eyes and in donor tissue from AMD patients. Mechanistically, we found an age-dependent shift in NURR1 dimerization from NURR1-RXRα heterodimers toward NURR1-NURR1 homodimers in primary human RPE cells. Additionally, overexpression and activation of NURR1 attenuated TNF-α-induced epithelial-to-mesenchymal transition (EMT) and migration, and modulated EMT-associated gene and protein expression in human RPE cells independent of age. In vivo, oral administration of IP7e, a potent NURR1 activator, ameliorated EMT in an experimental model of wet AMD and improved retinal function in a mouse model that presents with dry AMD features, impacting AMD phenotype, structure, and function of RPE cells, inhibiting accumulation of immune cells, and diminishing lipid accumulation. These results provide insight into the mechanisms of action of NURR1 in the aging eye, and demonstrate that the relative expression levels and activity of NURR1 is critical for both physiological and pathological functions of human RPE cells through RXRα-dependent regulation, and that targeting NURR1 may have therapeutic potential for AMD by modulating EMT, inflammation, and lipid homeostasis.


Subject(s)
Epithelial-Mesenchymal Transition , Macular Degeneration , Nuclear Receptor Subfamily 4, Group A, Member 2 , Retinal Pigment Epithelium , Aged , Animals , Humans , Lipids , Macular Degeneration/metabolism , Macular Degeneration/pathology , Mice , Nuclear Receptor Subfamily 4, Group A, Member 2/chemistry , Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism , Phenotype , Protein Multimerization , Retinal Pigment Epithelium/metabolism
2.
Adv Exp Med Biol ; 1415: 207-213, 2023.
Article in English | MEDLINE | ID: mdl-37440035

ABSTRACT

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly in developed countries. It is a complex, multifactorial, progressive disease with diverse molecular pathways, including inflammation, regulating its pathogenesis. The myeloid marker CD68 is a protein highly expressed in circulating and tissue macrophages. Recent observations of immune markers in human AMD tissues have varied with some finding ectopic RPE cells in advanced AMD and others noting negligible numbers of CD68-positive cells. Additionally, animal models of retinal degeneration have shown upregulation of CD68, in a protective population of retinal microglia. Herein, we review the potential role of CD68 in regulating RPE health and inflammation in the sub-retinal space and discuss observations on its localization in a mouse model that presents with AMD-like features.


Subject(s)
Macular Degeneration , Retinal Degeneration , Mice , Animals , Humans , Aged , Retinal Pigment Epithelium/pathology , Retina/pathology , Macular Degeneration/pathology , Retinal Degeneration/pathology , Inflammation/metabolism
3.
Lab Invest ; 102(10): 1132-1142, 2022 10.
Article in English | MEDLINE | ID: mdl-35589984

ABSTRACT

Apolipoprotein B100 (apoB100) is the structural protein of cholesterol carriers including low-density lipoproteins. It is a constituent of sub-retinal pigment epithelial (sub-RPE) deposits and pro-atherogenic plaques, hallmarks of early dry age-related macular degeneration (AMD), an ocular neurodegenerative blinding disease, and cardiovascular disease, respectively. Herein, we characterized the retinal pathology of transgenic mice expressing mouse apoB100 in order to catalog their functional and morphological ocular phenotypes as a function of age and establish measurable endpoints for their use as a mouse model to test potential therapies. ApoB100 mice were found to exhibit an age-related decline in retinal function, as measured by electroretinogram (ERG) recordings of their scotopic a-wave, scotopic b-wave; and c-wave amplitudes. ApoB100 mice also displayed a buildup of the cholesterol carrier, apolipoprotein E (apoE) within and below the supporting extracellular matrix, Bruch's membrane (BrM), along with BrM thickening, and accumulation of thin diffuse electron-dense sub-RPE deposits, the severity of which increased with age. Moreover, the combination of apoB100 and advanced age were found to be associated with RPE morphological changes and the presence of sub-retinal immune cells as visualized in RPE-choroid flatmounts. Finally, aged apoB100 mice showed higher levels of circulating and ocular pro-inflammatory cytokines, supporting a link between age and increased local and systemic inflammation. Collectively, the data support the use of aged apoB100 mice as a platform to evaluate potential therapies for retinal degeneration, specifically drugs intended to target removal of lipids from Bruch's membrane and/or alleviate ocular inflammation.


Subject(s)
Macular Degeneration , Retinal Degeneration , Animals , Apolipoproteins E , Cholesterol/metabolism , Cytokines/metabolism , Disease Models, Animal , Inflammation/metabolism , Lipoproteins, LDL/metabolism , Macular Degeneration/genetics , Mice , Mice, Transgenic , Retinal Pigment Epithelium/metabolism , Retinal Pigments/metabolism
4.
Mod Pathol ; 35(2): 165-176, 2022 02.
Article in English | MEDLINE | ID: mdl-34389792

ABSTRACT

A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer's disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics. We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Additionally, OPN puncta colocalized with an AMD risk-associated complement pathway protein, but not with apolipoprotein E or vitronectin, two other well-established basal deposit components. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina. Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN in the posterior pole as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.


Subject(s)
Macular Degeneration , Osteopontin , Aging/pathology , Biomarkers , Humans , Macular Degeneration/genetics , Macular Degeneration/metabolism , Macular Degeneration/pathology , Retina/metabolism , Retina/pathology
5.
Exp Eye Res ; 225: 109254, 2022 12.
Article in English | MEDLINE | ID: mdl-36150544

ABSTRACT

Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an exponential increase in pathologic molecular and cellular events that can induce senescence, traditionally defined as an irreversible loss of the cells' ability to divide and most recently reported to also occur in select post-mitotic and terminally differentiated cells, such as neurons. Together these facts raise the question as to whether or not cellular senescence, may play a role in the development of AMD. A number of studies have reported the effect of ocular-relevant inducers of senescence using primarily in vitro models of poorly polarized, actively dividing retinal pigment epithelial (RPE) cell lines. However, in interpretating the data, the fidelity of these culture models to the RPE in vivo, must be considered. Fewer studies have explored the presence and/or impact of senescent cells in in vivo models that present with phenotypic features of AMD, leaving this an open field for further investigation. The goal of this review is to discuss current thoughts on the potential role of senescence in AMD development and progression, with consideration of the model systems used and their relevance to human disease.


Subject(s)
Macular Degeneration , Retinal Pigment Epithelium , Middle Aged , Humans , Aged , Retinal Pigment Epithelium/metabolism , Macular Degeneration/metabolism , Cellular Senescence
6.
Exp Eye Res ; 222: 109170, 2022 09.
Article in English | MEDLINE | ID: mdl-35835183

ABSTRACT

Age-related macular degeneration (AMD) is a disease that affects the macula - the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by the presence of lipid- and protein-rich extracellular deposits beneath the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative "dry" stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients' vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly betweendifferent models and culture conditions used in different labs, which would directly impact their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.


Subject(s)
Geographic Atrophy , Induced Pluripotent Stem Cells , Macular Degeneration , Adult , Aged , Animals , Cell Culture Techniques , Geographic Atrophy/pathology , Humans , Induced Pluripotent Stem Cells/metabolism , Macular Degeneration/metabolism , Mice , Retinal Pigment Epithelium/metabolism , Swine
7.
Int J Mol Sci ; 21(18)2020 Sep 16.
Article in English | MEDLINE | ID: mdl-32947781

ABSTRACT

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which senses environmental, dietary or metabolic signals to mount a transcriptional response, vital in health and disease. As environmental stimuli and metabolic products have been shown to impact the central nervous system (CNS), a burgeoning area of research has been on the role of the AHR in ocular and non-ocular neurodegenerative diseases. Herein, we summarize our current knowledge, of AHR-controlled cellular processes and their impact on regulating pathobiology of select ocular and neurodegenerative diseases. We catalogue animal models generated to study the role of the AHR in tissue homeostasis and disease pathogenesis. Finally, we discuss the potential of targeting the AHR pathway as a therapeutic strategy, in the context of the maladies of the eye and brain.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , Eye Diseases/metabolism , Molecular Targeted Therapy , Neurodegenerative Diseases/metabolism , Receptors, Aryl Hydrocarbon/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/agonists , Biotransformation , Central Nervous System/cytology , Central Nervous System/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/physiology , Disease Models, Animal , Eye Diseases/drug therapy , Eye Diseases/genetics , Eye Proteins/physiology , Gene Expression Regulation , Helix-Loop-Helix Motifs , Humans , Ligands , Mammals/metabolism , Multiple Sclerosis/drug therapy , Nerve Degeneration , Nerve Tissue Proteins/physiology , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/genetics , Parkinson Disease/metabolism , Polychlorinated Dibenzodioxins/pharmacology , Quinolones/pharmacology , Quinolones/therapeutic use , Rats , Receptors, Aryl Hydrocarbon/agonists , Signal Transduction/physiology , Transcription, Genetic , Xenobiotics/metabolism
8.
Int J Mol Sci ; 21(8)2020 Apr 21.
Article in English | MEDLINE | ID: mdl-32326149

ABSTRACT

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. Therefore, the identification of key regulators of these vascular processes is critical to identifying therapeutic means by which to target vascular-associated compromises and complications. Nuclear receptors are a family of transcription factors that have been shown to be involved in modulating different aspects of vascular biology in many tissues systems. Most recently, the role of nuclear receptors in ocular biology and vasculopathies has garnered interest. Herein, we review studies that have used in vitro assays and in vivo models to investigate nuclear receptor-driven pathways in two ocular vascular diseases associated with blindness, wet or exudative age-related macular degeneration, and proliferative diabetic retinopathy. The potential therapeutic targeting of nuclear receptors for ocular diseases is also discussed.


Subject(s)
Disease Susceptibility , Neovascularization, Pathologic/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Biomarkers , Disease Management , Humans , Immunohistochemistry , Macular Degeneration/etiology , Macular Degeneration/metabolism , Macular Degeneration/pathology , Molecular Targeted Therapy , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Retinal Neovascularization/etiology , Retinal Neovascularization/metabolism , Retinal Neovascularization/pathology , Signal Transduction
10.
Adv Exp Med Biol ; 1185: 9-13, 2019.
Article in English | MEDLINE | ID: mdl-31884581

ABSTRACT

Age-related macular degeneration (AMD) continues to be the leading cause of visual impairment for the elderly in developed countries. It is a complex, multifactorial, progressive disease with diverse molecular pathways regulating its pathogenesis. One of the cardinal features of the early clinical subtype of AMD is the accumulation of lipid- and protein-rich deposits within Bruch's membrane, called drusen, which can be visualized by fundus imaging. Currently, multiple in vitro and in vivo model systems exist, which can be used to help tease out mechanisms associated with different molecular pathways driving disease initiation and progression. Given the lack of treatments for patients suffering from the dry form of AMD, it is imperative to appreciate the different known morphological endpoints associated with the various pathogenic pathways, in order to derive further insights, for the ultimate purpose of disease modeling and development of effective therapeutic interventions.


Subject(s)
Bruch Membrane/pathology , Macular Degeneration/pathology , Retina/pathology , Aged , Humans
11.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt A): 1583-1595, 2018 May.
Article in English | MEDLINE | ID: mdl-29481912

ABSTRACT

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor, initially discovered for its role in regulating xenobiotic metabolism. There is extensive evidence supporting a multi-faceted role for AhR, modulating physiological pathways important in cell health and disease. Recently we demonstrated that the AhR plays a role in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that loss of AhR exacerbates choroidal neovascular (CNV) lesion formation in a murine model. Herein we tested the therapeutic impact of AhR activation on CNV lesion formation and factors associated with aberrant neovascularization. We screened a panel of synthetic drugs and endogenous AhR ligands, assessed their ability to activate AhR in choroidal endothelial cells, and inhibit angiogenesis in vitro. Drugs with an anti-angiogenic profile were then administered to a murine model of CNV. Two compounds, leflunomide and flutamide, significantly inhibited CNV formation concurrent with positive modifying effects on angiogenesis, inflammation, extracellular matrix remodeling, and fibrosis. These results validate the role of the AhR pathway in regulating CNV pathogenesis, identify mechanisms of AhR-based therapies in the eye, and argue in favor of developing AhR as a drug target for the treatment of neovascular AMD.


Subject(s)
Choroidal Neovascularization/metabolism , Choroidal Neovascularization/prevention & control , Endothelial Cells/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Animals , Cell Line , Choroidal Neovascularization/genetics , Choroidal Neovascularization/pathology , Endothelial Cells/pathology , Macaca mulatta , Macular Degeneration/genetics , Macular Degeneration/metabolism , Macular Degeneration/pathology , Macular Degeneration/prevention & control , Mice , Mice, Knockout , Receptors, Aryl Hydrocarbon/genetics
12.
Exp Eye Res ; 162: 62-72, 2017 09.
Article in English | MEDLINE | ID: mdl-28629927

ABSTRACT

The mouse is one of the most commonly used mammalian systems to study human diseases. In particular it has been an invaluable tool to model a multitude of ocular pathologies affecting the posterior pole. The aim of this study was to create a comprehensive map of the ultrastructure of the mouse posterior pole using the quick-freeze/deep-etch method (QFDE). QFDE can produce detailed three-dimensional images of tissue structure and macromolecular moieties, without many of the artifacts introduced by structure-altering post-processing methods necessary to perform conventional transmission electron microscopy (cTEM). A total of 18 eyes from aged C57BL6/J mice were enucleated and the posterior poles were processed, either intact or with the retinal pigment epithelium (RPE) cell layer removed, for imaging by either QFDE or cTEM. QFDE images were correlated with cTEM cross-sections and en face images through the outer retina. Nicely preserved outer retinal architecture was observed with both methods, however, QFDE provided excellent high magnification imaging, with greater detail, of the apical, central, and basal planes of the RPE. Furthermore, key landmarks within Bruch's membrane, choriocapillaris, choroid and sclera were characterized and identified. In this study we developed methods for preparing the outer retina of the mouse for evaluation with QFDE and provide a map of the ultrastructure and cellular composition of the outer posterior pole. This technique should be applicable for morphological evaluation of mouse models, in which detailed visualization of subtle ocular structural changes is needed or in cases where post-processing methods introduce unacceptable artifacts.


Subject(s)
Choroid/ultrastructure , Microscopy, Electron, Transmission/methods , Pigment Epithelium of Eye/ultrastructure , Sclera/ultrastructure , Animals , Bruch Membrane/ultrastructure , Female , Imaging, Three-Dimensional , Male , Mice , Mice, Inbred C57BL , Models, Animal
14.
J Pathol ; 235(1): 101-12, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25186463

ABSTRACT

The aryl hydrocarbon receptor (AhR) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the AhR signalling pathway in the pathogenesis of the wet, neovascular subtype of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly in the Western world. Comparative analysis of gene expression profiles of aged AhR(-/-) and wild-type (wt) mice, using high-throughput RNA sequencing, revealed differential modulation of genes belonging to several AMD-related pathogenic pathways, including inflammation, angiogenesis and extracellular matrix regulation. To investigate AhR regulation of these pathways in wet AMD, we experimentally induced choroidal neovascular lesions in AhR(-/-) mice and found that they measured significantly larger in area and volume compared to age-matched wt mice. Furthermore, these lesions displayed a higher number of ionized calcium-binding adaptor molecule 1-positive (Iba1(+) ) microglial cells and a greater amount of collagen type IV deposition, events also seen in human wet AMD pathology specimens. Consistent with our in vivo observations, AhR knock-down was sufficient to increase choroidal endothelial cell migration and tube formation in vitro. Moreover, AhR knock-down caused an increase in collagen type IV production and secretion in both retinal pigment epithelial (RPE) and choroidal endothelial cell cultures, increased expression of angiogenic and inflammatory molecules, including vascular endothelial growth factor A (VEGFA) and chemokine (C-C motif) ligand 2 (CCL2) in RPE cells, and increased expression of secreted phosphoprotein 1 (SPP1) and transforming growth factor-ß1 (TGFß1) in choroidal endothelial cells. Collectively, our findings identify AhR as a regulator of multiple pathogenic pathways in experimentally induced choroidal neovascularization, findings that are consistent with a possible role of AhR in wet AMD. The data discussed in this paper have been deposited in NCBI's Gene Expression Omnibus; GEO Submission No. GSE56983, NCBI Tracking System No. 17021116.


Subject(s)
Choroidal Neovascularization/genetics , Gene Expression Regulation/genetics , Receptors, Aryl Hydrocarbon/genetics , Retinal Pigment Epithelium/metabolism , Animals , Cell Movement/genetics , Cells, Cultured , Choroid , Choroidal Neovascularization/metabolism , Humans , Macular Degeneration/genetics , Macular Degeneration/immunology , Mice, Inbred C57BL , Mice, Knockout , Receptors, Aryl Hydrocarbon/metabolism , Retinal Pigment Epithelium/immunology , Vascular Endothelial Growth Factor A/metabolism
15.
Adv Exp Med Biol ; 854: 45-51, 2016.
Article in English | MEDLINE | ID: mdl-26427392

ABSTRACT

Age-related macular degeneration (AMD) is the leading cause of legal blindness and visual impairment in individuals over 60 years of age in the Western World. A common morphological denominator in all forms of AMD is the accumulation of microglia within the sub-retinal space, which is believed to be a contributing factor to AMD progression. However, the signaling pathway and molecular players regulating microglial recruitment have not been completely identified. Multiple in-vitro and in-vivo studies, to date, have highlighted the contributions of nuclear receptor ligands in the treatment of inflammation related disorders such as atherosclerosis and Alzheimer's disease. Given that inflammation and the immune response play a vital role in the initiation and progression of AMD, in this brief review we will highlight some of these studies with a particular focus on the lipid activated "adopted orphan" nuclear receptors, the liver x receptors (LXRs) and the peroxisome proliferator-activated receptors (PPARs). The results of these studies strongly support the rationale that treatment with LXR and PPAR ligands may ameliorate microglial activation in the sub-retinal space and ultimately slow down or reverse the progression of AMD.


Subject(s)
Macular Degeneration/metabolism , Microglia/metabolism , Orphan Nuclear Receptors/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Animals , Humans , Inflammation/metabolism , Liver X Receptors , Retinal Pigment Epithelium/metabolism , Signal Transduction
16.
Proc Natl Acad Sci U S A ; 110(43): E4069-78, 2013 Oct 22.
Article in English | MEDLINE | ID: mdl-24106308

ABSTRACT

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR(-/-) mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR(-/-) mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.


Subject(s)
Aging/metabolism , Disease Models, Animal , Macular Degeneration/metabolism , Pigment Epithelium of Eye/metabolism , Receptors, Aryl Hydrocarbon/deficiency , Adolescent , Adult , Aging/genetics , Aging/pathology , Animals , Bruch Membrane/metabolism , Bruch Membrane/pathology , Bruch Membrane/ultrastructure , Cell Line , Child , Extracellular Matrix/metabolism , Female , Humans , Lipofuscin/metabolism , Lipoproteins, LDL/blood , Lipoproteins, LDL/metabolism , Macular Degeneration/genetics , Macular Degeneration/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron , Middle Aged , Pigment Epithelium of Eye/pathology , Pigment Epithelium of Eye/ultrastructure , RNA Interference , Receptors, Aryl Hydrocarbon/genetics , Tight Junctions/metabolism , Tight Junctions/pathology , Young Adult
17.
Cell Mol Life Sci ; 71(23): 4617-36, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25156067

ABSTRACT

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly in the Western world. Over the last 30 years, our understanding of the pathogenesis of the disease has grown exponentially thanks to the results of countless epidemiology, genetic, histological, and biochemical studies. This information, in turn, has led to the identification of multiple biologic pathways potentially involved in development and progression of AMD, including but not limited to inflammation, lipid and extracellular matrix dysregulation, and angiogenesis. Nuclear receptors are a superfamily of transcription factors that have been shown to regulate many of the pathogenic pathways linked with AMD and as such they are emerging as promising targets for therapeutic intervention. In this review, we will present the fundamental phenotypic features of AMD and discuss our current understanding of the pathobiological disease mechanisms. We will introduce the nuclear receptor superfamily and discuss the current literature on their effects on AMD-related pathophysiology.


Subject(s)
Macular Degeneration/metabolism , Macular Degeneration/pathology , Receptors, Cytoplasmic and Nuclear/metabolism , Retina/pathology , Aging , Animals , Humans , Inflammation/complications , Macular Degeneration/etiology , Macular Degeneration/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Retina/metabolism , Signal Transduction
18.
Adv Exp Med Biol ; 801: 317-21, 2014.
Article in English | MEDLINE | ID: mdl-24664713

ABSTRACT

Age-related macular degeneration (AMD) is the most important cause of blindness and visual impairment among the elderly. Nuclear receptors represent one of the largest families of transcription factors, with 48 present in the human genome. They are critical regulators and modulators of developmental and physiological processes and are both targets of drugs and chemicals of environmental significance. Many of the cellular processes regulated by nuclear receptors are disrupted in AMD. With this in mind, we recently created a nuclear receptor atlas of retinal pigment epithelial (RPE) cells, cells affected in AMD, highlighting the expression of all the nuclear receptors. The results of which provided scaffold to study individual receptors in aging and disease. This study led to several candidate receptors that have become the focus of detailed studies regarding their mechanistic role in the eye. One example of a nuclear receptor potentially relevant to AMD pathobiology is presented.


Subject(s)
Macular Degeneration/drug therapy , Macular Degeneration/physiopathology , Receptors, Aryl Hydrocarbon/physiology , Receptors, Cytoplasmic and Nuclear/physiology , Retinal Pigment Epithelium/physiopathology , Animals , Cell Line , Drug Design , Humans , Mice , Mice, Knockout , Receptors, Aryl Hydrocarbon/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Retinal Pigment Epithelium/cytology
19.
Curr Opin Pharmacol ; 75: 102439, 2024 04.
Article in English | MEDLINE | ID: mdl-38447458

ABSTRACT

To develop effective therapies for complex blinding diseases such as age-related macular degeneration (AMD), identification of mechanisms involved in its initiation and progression is needed. The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor that regulates several AMD-associated pathogenic pathways. However, it has not been investigated in detail in the ocular posterior pole during aging or in AMD. This review delves into the literature highlighting the significance of ESRRA as a molecular target that may be important in the pathobiology of AMD, and discusses data available supporting the targeting of this receptor signaling pathway as a therapeutic option for AMD.


Subject(s)
ERRalpha Estrogen-Related Receptor , Macular Degeneration , Humans , Macular Degeneration/drug therapy , Macular Degeneration/metabolism , Macular Degeneration/pathology , Aging/physiology , Receptors, Cytoplasmic and Nuclear , Eye/metabolism
20.
STAR Protoc ; 5(3): 103150, 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-39002132

ABSTRACT

During aging and in retinal degenerative diseases, vulnerable retinal pigment epithelial (RPE) cells are subject to mitochondrial dysfunction, creating a need for accessibility to tools which can facilitate assessment of the ocular posterior pole bioenergetics. Here, we present a protocol for quantifying mitochondrial respiration in the posterior eye cup (RPE-choroid-sclera) of young and old mice. We describe steps for eye cup dissection, optimization of tissue size, drug concentrations, and cycle conditions using the XF Cell Mito Stress Test.

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