Optometry Commons^™

Atypical Haemorrhagic Presentation Of Neuro-Retinitis And Serous Retinal Detachment Secondary To Cat-Scratch Disease, Henry C Skrehot, Amer F Alsoudi, Ryan P Nolan, Adam J Cantor, Asad Loya, Rod Foroozan

Faculty, Staff and Students Publications

Cat-scratch disease (CSD) is a self-limited disease caused by Bartonella henselae, a fastidious gram-negative intracellular bacillus bacterium. Neuroretinitis, a form of optic neuropathy characterised clinically by optic disc swelling and a macular star, is an uncommon manifestation of CSD occurring in approximately 1-2% of cases. We report a case of a 14-year-old female who presented to the emergency department with a chief complaint of acute painless vision loss described as a large black spot in the centre of her right eye vision 2 weeks after being scratched by cats. Fundus examination revealed Frisen grade 5 disc oedema with an …

The Co-Expression Of The Depolarizing And Hyperpolarizing Mechanosensitive Ion Channels In Mammalian Retinal Neurons, Vivian Y Pang, Zhuo Yang, Samuel M Wu, Ji-Jie Pang

Faculty, Staff and Students Publications

Introduction

The elevation of the intraocular and extraocular pressures is associated with various visual conditions, including glaucoma and traumatic retinal injury. The retina expresses mechanosensitive channels (MSCs), but the role of MSCs in retinal physiology and pathologies has been unclear.

Methods

Using immunocytochemistry, confocal microscopy, and patch-clamp recording techniques, we studied the co-expression of K⁺-permeable (K-MSCs) TRAAK and big potassium channel BK with the epithelial sodium channel ENaC and transient receptor potential channel vanilloid TPRV4 and TRPV2 favorably permeable to Ca²⁺ than Na⁺ (together named N-MSCs), and TRPV4 activity in the mouse retina.

Results

TRAAK immunoreactivity …

Trpv4 Affects Visual Signals In Photoreceptors And Rod Bipolar Cells, Ye Long, Maxim Kozhemyakin, Samuel M Wu, Ji-Jie Pang

Faculty, Staff and Students Publications

INTRODUCTION: Mechanical sensitive channels expressed in mammalian retinas are effectors of elevated pressure stresses, but it is unclear how their activation affects visual function in pressure-related retinal disorders.

METHODS: This study investigated the role of the transient potential channel vanilloid TRPV4 in photoreceptors and rod bipolar cells (RBCs) with immunohistochemistry, confocal microscopy, electroretinography (ERG), and patch-clamp techniques.

RESULTS: TRPV4 immunoreactivity (IR) was found in the outer segments of photoreceptors, dendrites and somas of PKCα-positive RBCs and other BCs, plexiform layers, and retinal ganglion cells (RGCs) in wild-type mice. TRPV4-IR was largely diminished in the retinas of homozygous TRPV4 transgenic mice. …

Single Cell Analysis Of Short-Term Dry Eye Induced Changes In Cornea Immune Cell Populations, Jehan Alam, Ebru Yaman, Gerda Cristal Villalba Silva, Rui Chen, Cinita S De Paiva, Mary Ann Stepp, Stephen C Pflugfelder

Faculty, Staff and Students Publications

BACKGROUND: Dry eye causes corneal inflammation, epitheliopathy and sensorineural changes. This study evaluates the hypothesis that dry eye alters the percentages and transcriptional profiles of immune cell populations in the cornea.

METHODS: Desiccating stress (DS) induced dry eye was created by pharmacologic suppression of tear secretion and exposure to drafty low humidity environment. Expression profiling of corneal immune cells was performed by single-cell RNA sequencing (scRNA-seq). Cell differentiation trajectories and cell fate were modeled through RNA velocity analysis. Confocal microscopy was used to immunodetect corneal immune cells. Irritation response to topical neurostimulants was assessed.

RESULTS: Twelve corneal immune cell populations …

The Utility Of Software-Detected Non-Invasive Tear Break-Up In Comparison To Fluorescein Tear Break-Up Measurements, Stephen C Pflugfelder, Yasushi Kikukawa, Shin Tanaka, Takuya Kosugi

Faculty, Staff and Students Publications

PURPOSE: The purpose of this study is to characterize and discuss the difference between software-detected non-invasive tear break-up time (NIBUT) and the traditional clinical method of fluorescein break-up time (FBUT).

METHODS: Tear interferometry with the KOWA DR-1α (Kowa, Japan) and a standardized comprehensive ocular surface/tear evaluation were performed in 307 eyes. Software-detected NIBUT in the KOWA DR-1α images and the investigator-detected FBUT were compared.

RESULTS: Software-detected NIBUT was significantly shorter than investigator-measured FBUT. NIBUT was 3.1 ± 2.5 s (mean ± SD), whereas FBUT was 4.8 ± 3.0 s. This difference was due to three different patterns or conditions: a …

Strategies To Enhance Remote Monitoring Adherence Among Patients With Cardiovascular Implantable Electronic Devices, Thomas L Rotering, Sylvia J Hysong, Katherine E Williams, Merritt H Raitt, Mary A Whooley, Sanket S Dhruva

Faculty, Staff and Students Publications

BACKGROUND: Remote monitoring (RM) of patients with cardiovascular implantable electronic devices (CIEDs) (pacemakers and implantable cardioverter-defibrillators) has a Class 1, Level of Evidence A Heart Rhythm Society recommendation. Yet RM adherence varies widely across settings, and factors associated with variation are not understood.

OBJECTIVE: The purpose of this study was to identify strategies for supporting RM across Veterans Health Administration (VHA) facilities.

METHODS: In a national evaluation, we surveyed and interviewed 27 nurses, medical instrument technicians, and advanced practice providers across 26 VHA facilities (following approximately 15,000 CIED patients). Participants were selected based on overall patient adherence by facility, which …

Conditional Deletion Of Cd25 In The Corneal Epithelium Reveals Sex Differences In Barrier Disruption, Anmar Abu-Romman, Kaitlin K Scholand, Sonali Pal-Ghosh, Zhiyuan Yu, Yashaswini Kelagere, Ghasem Yazdanpanah, Winston W-Y Kao, Vivien J Coulson-Thomas, Mary Ann Stepp, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: IL-2 promotes activation, clonal expansion, and deletion of T cells. IL-2 signals through its heterotrimeric receptor (IL-2R) consisting of the CD25, CD122 and CD132 chains. CD25 knockout (KO) mice develop Sjögren Syndrome-like disease. This study investigates whether corneal CD25/IL-2 signaling is critical for ocular health.

METHODS: Eyes from C57BL/6 mice were collected and prepared for immunostaining or in-situ hybridization. Bulk RNA sequencing was performed on the corneal epithelium from wild-type and CD25KO mice. We generated a conditional corneal-specific deletion of CD25 in the corneal epithelium (CD25

RESULTS: In C57BL/6 mice, CD25 mRNA was expressed in ocular tissues. Protein expression …

Single Cell Analysis Of Short-Term Dry Eye Induced Changes In Cornea Immune Cell Populations, Brandon D Ayres, Eric Donnenfeld, Marjan Farid, Ian Benjamin Gaddie, Preeya K Gupta, Edward Holland, Paul M Karpecki, Richard Lindstrom, Kelly K Nichols, Stephen C Pflugfelder, Christopher E Starr, Elizabeth Yeu

Faculty, Staff and Students Publications

BACKGROUND: Twelve ocular surface disease experts convened to achieve consensus about Demodex blepharitis (DB) using a modified Delphi panel process.

METHODS: Online surveys were administered using scaled, open-ended, true/false, and multiple-choice questions. Consensus for questions using a 1 to 9 Likert scale was predefined as median scores of 7-9 and 1-3. For other question types, consensus was achieved when 8 of 12 panellists agreed. Questions were randomized, and results of each survey informed the following survey.

RESULTS: Twelve practitioners comprised the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH). Following 3 surveys, experts agreed that DB is chronic (n …

Tnf Is A Critical Cytokine In Age-Related Dry Eye Disease, Yashaswini Kelagere, Kaitlin K Scholand, Erica N Dejong, Andrea I Boyd, Zhiyuan Yu, Roger A Astley, Michelle C Callegan, Dawn Me Bowdish, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Aging is a complex biological process that is characterized by low-grade inflammation, called inflammaging. Aging affects multiple organs including eye and lacrimal gland. Tumor necrosis factor (TNF) is a pleiotropic cytokine that participates in inflammation, activation of proteases such as cathepsin S, and formation of ectopic lymphoid organs. Using genetic and pharmacological approaches, we investigated the role of TNF in age-related dry eye disease, emphasizing the ocular surface and lacrimal gland inflammation. Our results show the increased protein and mRNA levels of TNF in aged lacrimal glands, accompanied by increased TNF, IL1β, IL-18, CCL5, CXCL1, IL-2, IL-2 receptor alpha (CD25), …

Spatial Organization Of The Mouse Retina At Single Cell Resolution By Merfish, Jongsu Choi, Jin Li, Salma Ferdous, Qingnan Liang, Jeffrey R Moffitt, Rui Chen

Faculty, Staff and Students Publications

The visual signal processing in the retina requires the precise organization of diverse neuronal types working in concert. While single-cell omics studies have identified more than 120 different neuronal subtypes in the mouse retina, little is known about their spatial organization. Here, we generated the single-cell spatial atlas of the mouse retina using multiplexed error-robust fluorescence in situ hybridization (MERFISH). We profiled over 390,000 cells and identified all major cell types and nearly all subtypes through the integration with reference single-cell RNA sequencing (scRNA-seq) data. Our spatial atlas allowed simultaneous examination of nearly all cell subtypes in the retina, revealing …

Characterization Of Vascular Morphology Of Neovascular Age-Related Macular Degeneration By Indocyanine Green Angiography, Anish Attarde, Thomas S Riad, Zhao Zhang, Manisha Ahir, Yingbin Fu

Faculty, Staff and Students Publications

Age-related macular degeneration (AMD) is a leading cause of blindness among older individuals, and its prevalence is rapidly increasing due to the aging population. Choroidal neovascularization (CNV) or wet AMD, which accounts for 10%-20% of all AMD cases, is responsible for an alarming 80%-90% of AMD-related blindness. Current anti-VEGF therapies show suboptimal responses in approximately 50% of patients. Resistance to anti-VEGF treatment in CNV patients is often associated with arteriolar CNV, while responders tend to have capillary CNV. While fluorescein angiography (FA) is commonly used to assess leakage patterns in wet AMD patients and animal models, it does not provide …

Effects Of Cathepsin S Inhibition In The Age-Related Dry Eye Phenotype, Jeremias G Galletti, Kaitlin K Scholand, Claudia M Trujillo-Vargas, Wolfgang Haap, Tiago Santos-Ferreira, Christoph Ullmer, Zhiyuan Yu, Cintia S De Paiva

Faculty, Staff and Students Publications

PURPOSE: Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss-/-) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease.

METHODS: Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet-Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify …

Βii-Spectrin Is Required For Synaptic Positioning During Retinal Development, Debalina Goswami-Sewell, Caitlin Bagnetto, Cesiah C Gomez, Joseph T Anderson, Akash Maheshwari, Elizabeth Zuniga-Sanchez

Faculty, Staff and Students Publications

Neural circuit assembly is a multistep process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here, we uncovered a new role for the cytoskeletal protein βII-spectrin in properly positioning presynaptic and postsynaptic neurons to the developing synaptic layer. Loss of βII-spectrin …

Anti-Scg3 Gene Therapy To Treat Choroidal Neovascularization In Mice, Chengchi Huang, Liyang Ji, Avinash Kaur, Hong Tian, Prabuddha Waduge, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Neovascular age-related macular degeneration (nAMD) with choroidal neovascularization (CNV) is a leading cause of blindness in the elderly in developed countries. The disease is currently treated with anti-angiogenic biologics, including aflibercept, against vascular endothelial growth factor (VEGF) but with limited efficacy, treatment resistance and requirement for frequent intravitreal injections. Although anti-VEGF gene therapy may provide sustained therapy that obviates multiple injections, the efficacy and side effects related to VEGF pathway targeting remain, and alternative strategies to block angiogenesis independently of VEGF are needed. We recently reported that secretogranin III (Scg3) induces only pathological angiogenesis through VEGF-independent pathways, and Scg3-neutralizing antibodies …

Accuracy Of Artificial Intelligence In Estimating Best-Corrected Visual Acuity From Fundus Photographs In Eyes With Diabetic Macular Edema, William Paul, Philippe Burlina, Rohita Mocharla, Neil Joshi, Zhuolin Li, Sophie Gu, Onnisa Nanegrungsunk, Kira Lin, Susan B Bressler, Cindy X Cai, Jun Kong, T Y Alvin Liu, Hadi Moini, Weiming Du, Fouad Amer, Karen Chu, Robert Vitti, Farshid Sepehrband, Neil M Bressler

Faculty, Staff and Students Publications

IMPORTANCE: Best-corrected visual acuity (BCVA) is a measure used to manage diabetic macular edema (DME), sometimes suggesting development of DME or consideration of initiating, repeating, withholding, or resuming treatment with anti-vascular endothelial growth factor. Using artificial intelligence (AI) to estimate BCVA from fundus images could help clinicians manage DME by reducing the personnel needed for refraction, the time presently required for assessing BCVA, or even the number of office visits if imaged remotely.

OBJECTIVE: To evaluate the potential application of AI techniques for estimating BCVA from fundus photographs with and without ancillary information.

DESIGN, SETTING, AND PARTICIPANTS: Deidentified color fundus …

Systemic Adverse Events Among Patients With Diabetes Treated With Intravitreal Anti-Vascular Endothelial Growth Factor Injections, Sidra Zafar, Annette Walder, Salim Virani, Kristin Biggerstaff, Silvia Orengo-Nania, Jonathan Chang, Roomasa Channa

Faculty, Staff and Students Publications

IMPORTANCE: Anti-vascular endothelial growth factor (VEGF) agents are currently the mainstay of treatment for diabetic retinopathy (DR). Although effective, data on their systemic safety remains inconclusive, particularly in high-risk patient groups.

OBJECTIVE: To explore the systemic safety of intravitreal anti-VEGF agents among patients with diabetes.

DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective, longitudinal population-based analysis of the Corporate Data Warehouse, a large-scale database of patients within the US Veteran Health Affairs. All patients 18 years and older with type 2 diabetes who were seen at any Veterans Affairs health care facility in the US between January 1, 2011, and …

Secretogranin Iii Selectively Promotes Vascular Leakage In The Deep Vascular Plexus Of Diabetic Retinopathy, Liyang Ji, Prabuddha Waduge, Yan Wu, Chengchi Huang, Avinash Kaur, Paola Oliveira, Hong Tian, Jinsong Zhang, J Timothy Stout, Christina Y Weng, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, induces mosaic patterns of vasculopathy that may be associated with spatial heterogeneity of intraretinal endothelial cells. We recently reported that secretogranin III (Scg3), a neuron-derived angiogenic and vascular leakage factor, selectively binds retinal vessels of diabetic but not healthy mice. Here, we investigated endothelial heterogeneity of three retinal vascular plexuses in DR pathogenesis and the therapeutic implications. Our unique in vivo ligand binding assay detected a 22.7-fold increase in Scg3 binding to retinal vessels of diabetic mice relative to healthy mice. Functional immunohistochemistry revealed that Scg3 predominantly binds …

Static Perimetry In The Rate Of Progression In Ush2a-Related Retinal Degeneration (Rush2a) Study: Assessment Through 2 Years, Jacque L Duncan, Peiyao Cheng, Maureen G Maguire, Allison A Ayala, David G Birch, Janet K Cheetham, Todd A Durham, Abigail T Fahim, Carel B Hoyng, Hiroshi Ishikawa, Michel Michaelides, Mark E Pennesi, José-Alain Sahel, Katarina Stingl, Christina Y Weng

Faculty, Staff and Students Publications

PURPOSE: To evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa.

DESIGN: Prospective, observational cohort study.

METHODS: A total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (V

RESULTS: The average …

An Ocular Th1 Immune Response Promotes Corneal Nerve Damage Independently Of The Development Of Corneal Epitheliopathy, Alexia Vereertbrugghen, Manuela Pizzano, Florencia Sabbione, Irene Angelica Keitelman, Carolina Maiumi Shiromizu, Douglas Vera Aguilar, Federico Fuentes, Cintia S De Paiva, Mirta Giordano, Analía Trevani, Jeremías G Galletti

Faculty, Staff and Students Publications

Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured …

The First Transcriptomic Atlas Of The Adult Lacrimal Gland Reveals Epithelial Complexity And Identifies Novel Progenitor Cells In Mice, Vanessa Delcroix, Olivier Mauduit, Hyun Soo Lee, Anastasiia Ivanova, Takeshi Umazume, Sarah M Knox, Cintia S De Paiva, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

The lacrimal gland (LG) secretes aqueous tears. Previous studies have provided insights into the cell lineage relationships during tissue morphogenesis. However, little is known about the cell types composing the adult LG and their progenitors. Using scRNAseq, we established the first comprehensive cell atlas of the adult mouse LG to investigate the cell hierarchy, its secretory repertoire, and the sex differences. Our analysis uncovered the complexity of the stromal landscape. Epithelium subclustering revealed myoepithelial cells, acinar subsets, and two novel acinar subpopulations: Tfrc^hi and Car6^hi cells. The ductal compartment contained Wfdc2+ multilayered ducts and an Ltf+ cluster formed …

Single-Cell Transcriptome Analysis Of Xenotransplanted Human Retinal Organoids Defines Two Migratory Cell Populations Of Nonretinal Origin, Ying V Liu, Clayton P Santiago, Akin Sogunro, Gregory J Konar, Ming-Wen Hu, Minda M Mcnally, Yu-Chen Lu, Miguel Flores-Bellver, Silvia Aparicio-Domingo, Kang V Li, Zhuo-Lin Li, Dzhalal Agakishiev, Sarah E Hadyniak, Katarzyna A Hussey, Tyler J Creamer, Linda D Orzolek, Derek Teng, M Valeria Canto-Soler, Jiang Qian, Zheng Jiang, Robert J Johnston, Seth Blackshaw, Mandeep S Singh

Faculty, Staff and Students Publications

Human retinal organoid transplantation could potentially be a treatment for degenerative retinal diseases. How the recipient retina regulates the survival, maturation, and proliferation of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice and conducted histology and single-cell RNA sequencing alongside time-matched cultured retinal organoids. Unexpectedly, we observed human cells that migrated into all recipient retinal layers and traveled long distances. Using an unbiased approach, we identified these cells as astrocytes and brain/spinal cord-like neural precursors that were absent or rare in stage-matched cultured organoids. In contrast, retinal progenitor-derived rods and cones remained in the …

Epidemiology Of Retinopathy Of Prematurity In The Us From 2003 To 2019, Anshul Bhatnagar, Henry C Skrehot, Amit Bhatt, Honey Herce, Christina Y Weng

Faculty, Staff and Students Publications

IMPORTANCE: Retinopathy of prematurity (ROP) is a potentially blinding retinal disease with poorly defined epidemiology. Understanding of which infants are most at risk for developing ROP may foster targeted detection and prevention efforts.

OBJECTIVE: To identify changes in ROP incidence in the US from 2003 to 2019.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective database cohort study used the Healthcare Cost and Utilization Project Kids' Inpatient Databases. These nationwide databases are produced every 3 years, include data from over 4000 hospitals, and are designed to generate national estimates of health care trends in the US. Participants included pediatric newborns at risk …

Induction Of Innate Inflammatory Pathways In The Corneal Epithelium In The Desiccating Stress Dry Eye Model, Zhiyuan Yu, Ghasem Yazdanpanah, Jehan Alam, Cintia S De Paiva, Stephen Pflugfelder

Faculty, Staff and Students Publications

PURPOSE: To determine whether 24-hour exposure to the desiccating stress (DS) dry eye model induces NF-kB and NLRP3 inflammasome pathways in the mouse cornea epithelium.

METHODS: Six- to 8-week-old C57BL/6J mice were housed under normal humidity (nonstressed) or subjected to DS from a drafty, low-humidity environment combined with subcutaneous scopolamine four times/day for one day to suppress tear production (DS1). Cornea whole mounts were prepared for immunofluorescent staining, or the corneal epithelium was scraped for NF-kB p-p65 ELISA, Western blot, or real-time PCR to detect NF-kB and inflammasome pathway proteins and gene transcripts, respectively.

RESULTS: NF-kB phospho-p65 protein, nuclear NF-kB …

Light Responses And Amacrine Cell Modulation Of Morphologically-Identified Retinal Ganglion Cells In The Mouse Retina, Ji-Jie Pang, Fan Gao, Samuel M Wu

Faculty, Staff and Students Publications

By analyzing light-evoked spike responses, cation currents (ΔIC) and chloride currents (ΔICl) of over 100 morphologically-identified retinal ganglion cells (GCs) in dark-adapted mouse retina, we found there are at least 14 functionally- and morphologically-distinct types of RGCs. These cells can be divided into 5 groups based on their patterns of spike response to whole field light steps (SRWFLS), a GC identification scheme commonly used in studies with extracellular recording techniques. We also found that all GCs in the mouse retina express strychnine-sensitive glycine receptors, and receive light-elicited chloride current (ΔICl) accompanied by a conductance increase from narrow-field, glycinergic amacrine cells. …

Comparison Of Efficacy And Inflammatory Response To Thermoconjunctivoplasty Performed With Cautery Or Pulsed 1460 Nm Laser, Rodrigo Guimaraes De Souza, David Huang, Scott Prahl, Lauren Nakhleh, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Conjunctivochalasis is a degenerative condition of the conjunctiva that disrupts tear distribution and causes irritation. Thermoreduction of the redundant conjunctiva is required if symptoms are not relieved with medical therapy. Near-infrared laser treatment is a more controlled method to shrink the conjunctiva than thermocautery. This study compared tissue shrinkage, histology, and postoperative inflammation in thermoconjunctivoplasty performed on the mouse conjunctiva using either thermocautery or pulsed 1460 nm near-infrared laser irradiation. Three sets of experiments were performed on female C57BL/6J mice (

Ectopic Lymphoid Structures In The Aged Lacrimal Glands, Jeremias G Galletti, Kaitlin K Scholand, Claudia M Trujillo-Vargas, Zhiyuan Yu, Olivier Mauduit, Vanessa Delcroix, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Aging is a complex biological process in which many organs are pathologically affected. We previously reported that aged C57BL/6J had increased lacrimal gland (LG) lymphoid infiltrates that suggest ectopic lymphoid structures. However, these ectopic lymphoid structures have not been fully investigated. Using C57BL/6J mice of different ages, we analyzed the transcriptome of aged murine LGs and characterized the B and T cell populations. Age-related changes in the LG include increased differentially expressed genes associated with B and T cell activation, germinal center formation, and infiltration by marginal zone-like B cells. We also identified an age-related increase in B1

Lacrimal Gland Epithelial Cells Shape Immune Responses Through The Modulation Of Inflammasomes And Lipid Metabolism, Vanessa Delcroix, Olivier Mauduit, Menglu Yang, Amrita Srivastava, Takeshi Umazume, Cintia S De Paiva, Valery I Shestopalov, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren's syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren's syndrome models: diseased

Alternative Polyadenylation Transcriptome-Wide Association Study Identifies Apa-Linked Susceptibility Genes In Brain Disorders, Ya Cui, Frederick J Arnold, Fanglue Peng, Dan Wang, Jason Sheng Li, Sebastian Michels, Eric J Wagner, Albert R La Spada, Wei Li

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) plays an essential role in brain development; however, current transcriptome-wide association studies (TWAS) largely overlook APA in nominating susceptibility genes. Here, we performed a 3' untranslated region (3'UTR) APA TWAS (3'aTWAS) for 11 brain disorders by combining their genome-wide association studies data with 17,300 RNA-seq samples across 2,937 individuals. We identified 354 3'aTWAS-significant genes, including known APA-linked risk genes, such as SNCA in Parkinson's disease. Among these 354 genes, ~57% are not significant in traditional expression- and splicing-TWAS studies, since APA may regulate the translation, localization and protein-protein interaction of the target genes independent of mRNA level …

Molecular Mechanisms Regulating Wound Repair: Evidence For Paracrine Signaling From Corneal Epithelial Cells To Fibroblasts And Immune Cells Following Transient Epithelial Cell Treatment With Mitomycin C, Sonali Pal-Ghosh, Beverly A Karpinski, Himani Datta Majumdar, Trisha Ghosh, Julie Thomasian, Stephen R Brooks, Andrew P Sawaya, Maria I Morasso, Kaitlin K Scholand, Cintia S De Paiva, Jeremias G Galletti, Mary Ann Stepp

Faculty, Staff and Students Publications

In this paper, we use RNAseq to identify senescence and phagocytosis as key factors to understanding how mitomyin C (MMC) stimulates regenerative wound repair. We use conditioned media (CM) from untreated (CMC) and MMC treated (CMM) human and mouse corneal epithelial cells to show that corneal epithelial cells indirectly exposed to MMC secrete elevated levels of immunomodulatory proteins including IL-1α and TGFβ1 compared to cells exposed to CMC. These factors increase epithelial and macrophage phagocytosis and promote ECM turnover. IL-1α supplementation can increase phagocytosis in control epithelial cells and attenuate TGFβ1 induced αSMA expression by corneal fibroblasts. Yet, we show …

Fluorescence Angiography With Dual Fluorescence For The Early Detection And Longitudinal Quantitation Of Vascular Leakage In Retinopathy, Benjamin Pomeroy, Alexander W Venanzi, Wei Li, Abigail S Hackam, Midhat H Abdulreda

Faculty, Staff and Students Publications

BACKGROUND: Diabetic retinopathy (DR) afflicts more than 93 million people worldwide and is a leading cause of vision loss in working adults. While DR therapies are available, early DR development may go undetected without treatment due to the lack of sufficiently sensitive tools. Therefore, early detection is critically important to enable efficient treatment before progression to vision-threatening complications. A major clinical manifestation of early DR is retinal vascular leakage that may progress from diffuse to more localized focal leakage, leading to increased retinal thickness and diabetic macular edema (DME). In preclinical research, a hallmark of DR in mouse models is …