Biology subjects

Corson, T. W.

Publications and source records attributed to Corson, T. W..

6 recordsLinked to original sources

bioRxiv2025

Long-term Dietary Fat Intervention Affects Retinal Health in APOE Mice

The APOE genotype influences metabolic and neurodegenerative outcomes, with APOE4 carriers at higher risk for Alzheimers disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/ function in APOE3-knock-in (KI, neutral for AD) and APOE4-KI mice. Humanized APOE3 and APOE4-KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in APOE4 mice (2 months); APOE3 mice showed impairment only after prolonged exposure (6-12 months). Notably, WD-fed APOE3 mice exhibited more pronounced hyperlipidemia than APOE4 mice. APOE4 CD mice displayed early retinal thinning (6 months), while APOE4 WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in APOE4 mice, with increased tortuosity and reduced vascular area. Elevated Il1b expression in WD-fed APOE4 mice confirmed inflammation-associated retinal dysfunction. APOE4 mice showed heightened vulnerability to diet, with WD worsening metabolic, retinal, and vascular impairments. While CD improved glucose metabolism, it did not prevent retinal dysfunction. These findings underscore genotype-specific dietary strategies to mitigate APOE4-associated risks.

neuroscience↗

bioRxiv2022

PRMT5 is a therapeutic target in choroidal neovascularization

Ocular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-{kappa}B), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-{kappa}B. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-{kappa}B activity and the expression of its target genes, such as tumor necrosis factor (TNF-) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G1/S-phase in a dose-dependent manner in these cells. Thus, we provide the first evidence that inhibition of PRMT5 impedes angiogenesis in ocular endothelial cells, suggesting PRMT5 as a potential therapeutic target to ameliorate ocular neovascularization.

pharmacology and toxicology↗

bioRxiv2020

Building a virtual summer research experience in cancer for high school and early undergraduate students: lessons from the COVID-19 pandemic

BackgroundThe COVID-19 pandemic posed a unique challenge for summer research programs in 2020, particularly for programs aimed at hands-on experience for younger trainees. The Indiana University Melvin and Bren Simon Comprehensive Cancer Center supports two pipeline programs, which traditionally immerse high school juniors, seniors, and early undergraduate students from underrepresented populations in science in hands-on projects in cancer biology labs. However, due to social distancing policies during the pandemic and reduction of research operations, these students were not physically allowed on campus. Thus, the authors set out to strategically pivot to a wholly virtual curriculum and evaluate the Virtual Summer Research Experience in Cancer outcomes. MethodsThe virtual program included four components: 1. a core science and professional development curriculum led by high school teachers and senior undergraduates; 2. faculty-delivered didactic sessions on cancer science; 3. mentored, virtual research projects with research faculty; and 4. online networking events to encourage vertical mentoring. Outcomes data were measured using an 11-item Research Preparation scale, daily electronic feedback, and structured evaluation and feedback via Zoom weekly. ResultsOutcome data suggested high self-reported satisfaction with the virtual program. Outcome data also revealed the importance of coordination between multiple entities for seamless program implementation. This includes the active recruitment and participation of high school teachers and further investment in information technology capabilities of institutions. ConclusionsFindings reveal a path to educate and train high school and early undergraduate students in cancer research when hands-on, in-person training is not feasible. Virtual research experiences are not only useful to engage students during public health crises but can provide an avenue for cancer centers to expand their cancer education footprints to remotely located schools and universities with limited resources to provide such experiences to their students.

scientific communication and education↗

bioRxiv2020

Ferrochelatase regulates retinal neovascularization

Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen-induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co-localized with neovascular tufts. Partial loss-of-function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N-methyl protoporphyrin had similar effects. Griseofulvin is an anti-fungal drug that inhibits FECH as an off-target effect. Strikingly, intravitreal griseofulvin blocked pathological tuft formation and revascularized areas of vasoobliteration faster than vehicle, suggesting potential as a FECH-targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.Competing Interest StatementS. Pran Babu and T. W. Corson are named inventors on patent applications related to this work.AbbreviationsBSAbovine serum albuminDAIdays after injectionDMSOdimethyl sulfoxideEdU5-ethynyl-2′-deoxyuridine (EdU)ERGelectroretinogrameNOSendothelial nitric oxide synthaseEPPerythropoietic protoporphyriaETCelectron transport chainFAfluorescein angiographyFECHferrochelataseGCLganglion cell layerGFAPglial fibrillary acidic proteinGS-IB4Griffonia simplicifolia isolectin B4H&Ehematoxylin and eosinHIF-1hypoxia inducible factor 1HO-1heme oxygenase 1INLinner nuclear layerNMPPN-methyl protoporphyrinOCToptical coherence tomographyOIRoxygen induced retinopathyONLouter nuclear layerPBSphosphate buffered salinePDRproliferative diabetic retinopathyPFAparaformaldehydePPIXprotoporphyrin IXROPretinopathy of prematurityVEGFvascular endothelial growth factorView Full Text

pathology↗

bioRxiv2019

Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction

The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis. O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/836304v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1820147org.highwire.dtl.DTLVardef@21fad6org.highwire.dtl.DTLVardef@db22c1org.highwire.dtl.DTLVardef@c6ae5e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHeme synthesis inhibition changes mitochondrial morphology in endothelial cells C_LIO_LILoss of heme causes a buildup of mitochondrial ROS and depolarized membrane potential C_LIO_LIEndothelial cells have defective oxidative phosphorylation and glycolysis on loss of heme C_LIO_LIMitochondrial damage is caused by loss of functional heme-containing Complex IV and partially restored by exogenous heme C_LI

cell biology↗

bioRxiv2018

Ref-1/APE1 inhibition with novel small molecules blocks ocular neovascularization

Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF-{kappa}B and other pro-angiogenic transcription factors. An existing inhibitor of Ref-1s function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared to APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 M, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a GI50 APX2009: 26 M, APX2014: 5.0 M). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid nanomolar concentrations compared to control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-{kappa}B activation and downstream targets. Ex vivo, both APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared to vehicle (p < 0.0001, ANOVA with Dunnetts post hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesis in vitro and ex vivo, and APX2009 is an effective systemic therapy for CNV in vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.

pharmacology and toxicology↗