Biology subjects

Massengill, M. T.

Publications and source records attributed to Massengill, M. T..

3 recordsLinked to original sources

bioRxiv2023

Modulation of Retinal Inflammation Delays Degeneration in a Mouse Model of Geographic Atrophy

The advanced form of AMD, geographic atrophy, is associated with increased RPE oxidative stress and chronic inflammation. Here we evaluated the effects of delivering an anti-inflammatory viral gene by an AAV-vector in a mouse model of geographic atrophy. We measured changes in retinal function, structure, and morphology over nine months with electroretinography, optical coherence tomography, and fundoscopy, respectively. In addition, we used retinal tissue to quantify changes in markers of inflammation by multiplex ELISA, RT-qPCR, and immunofluorescence staining. Our AAV significantly delayed the loss of retinal function and structure and decreased retinal inflammation compared to the control AAV treatment. Our results suggest that modulating retinal inflammation could significantly slow the progression of geographic atrophy.

neuroscience↗

bioRxiv2021

Binocular Benefit Following Monocular Subretinal AAV Injection in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa (adRP)

Autosomal dominant retinitis pigmentosa (adRP) is frequently caused by mutations in RHO, the gene for rhodopsin. In previous experiments in dogs with the T4R mutation in RHO, an AAV2/5 vector expressing both an shRNA directed to human and dog RHO mRNA and an shRNA-resistant human RHO cDNA (AAV-RHO820-shRNA820) prevented retinal degeneration for more than 8 months following injection. To confirm that this same vector could protect the retinas of a different species and bearing a different RHO mutation, we injected mice transgenic for human P23H RHO at postnatal day 30 in one eye. For nine months, we monitored their retinal structure using spectral- domain optical coherence tomography (SD-OCT) and retinal function using electroretinography (ERG). We compared these to P23H RHO transgenic mice injected with AAV-GFP. Though retinas continued to thin over time, compared to control injected eyes, AAV-RHO820-shRNA820 slowed the loss of photoreceptor cells and decreased ERG amplitudes in AAV-RHO820-shRNA820 eyes during the nine-month study period. Unexpectedly, we also observed preservation of retinal structure and function in the untreated contralateral eyes of AAV-RHO820-shRNA820 treated mice. PCR analysis and western blots provided evidence that a low amount of vector from injected eyes was present in uninjected eyes.

neuroscience↗

bioRxiv2018

A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis

We describe an immunosuppressive peptide corresponding to the kinase inhibitory region (KIR) of the intracellular checkpoint protein suppressor of cytokine signaling 1 (SOCS-1) that binds to the phospho-tyrosine containing regions of the tyrosine kinases JAK2 and TYK2 and the adaptor protein MAL, and thereby inhibits signaling downstream from these signaling mediators. The peptide, SOCS1-KIR, is thus capable of downregulating overactive JAK/STAT or NF-kB signaling in somatic cells, including those in many compartments of the eye. Attachment of poly-arginine to this peptide (R9-SOCS1-KIR) allows it to penetrate the plasma membrane in aqueous media. R9-SOCS1-KIR was tested in ARPE-19 cells and was found to attenuate mediators of inflammation by blocking the inflammatory effects of IFN{gamma}, TNF, or IL-17A. R9-SOCS1-KIR also protected against TNF or IL-17A mediated damage to the barrier properties of ARPE-19 cells, as evidenced by immunostaining with the tight junction protein, zona occludin 1 (ZO-1), and measurement of transepithelial electrical resistance (TEER). Experimental autoimmune uveitis (EAU) was generated in B10.RIII mice using a peptide of interphotoreceptor retinal binding protein (IRBP161-180) as immunogen. Topical administration of R9-SOCS1-KIR protected ocular structure and function as seen by fundoscopy, optical coherence tomography (OCT), and electroretinography (ERG). The ability R9-SOCS1-KIR to suppress ocular inflammation and preserve barrier properties of retinal pigment epithelium makes it a potential candidate for aqueous treatment of autoimmune uveitis.\n\nHighlightsO_LIpeptide corresponding to the kinase inhibitory region of SOCS-1 linked to poly-arginine (R9-SOCS1-KIR) and its inactive control peptide were chemically synthesized.\nC_LIO_LIR9-SOCS1-KIR attenuated pro-inflammatory effects of IFN{gamma}, TNF, and IL-17 in ARPE-19 cells, thus showing a simultaneous inhibition Th1 and Th17 cell functions.\nC_LIO_LIDamage to barrier properties of ARPE-19 cells caused by TNF or IL-17 was prevented in the presence of R9-SOCS1-KIR.\nC_LIO_LITopical administration of R9-SOCS1-KIR prevented ocular damage in a mouse model of experimental autoimmune uveitis.\nC_LI

immunology↗