Digital Commons Network^™

Development Of An Aav-Based Gene Therapy For The Ocular Phenotype Of Friedreich's Ataxia., Heyu Tang, Siddhant Gupte, Emily Xu, Kaitlyn R Calabro, Hannah Friend, Sean M Crosson, Diego Fajardo, Zachary Kostamo, Hangning Zhang, James J Peterson, Fangyu Lin, Zbynek Kozmik, Cathleen Lutz, Sanford L Boye, Shannon E Boye

Faculty Research 2026

Friedreich's ataxia (FA) is a leading form of hereditary ataxia caused by autosomal recessive mutations in frataxin (FXN). GAA triplet repeat expansions lead to lower levels of FXN expression, abnormal influx of iron into mitochondria, and damage to the nervous system. Patients typically present before the second decade with loss of muscular function, speech impediments, and cardiomyopathy. At later stages, vision loss typically manifests. Work is under way to develop gene therapies that address the cardiac and CNS manifestations, but their routes of administration do not lead to efficient transduction of the retina. The purpose of this study was to …

Targeting Pediatric Glioblastomas By Combining Olig2 Inhibitor Ct-179 With Fractionated Radiation In A Panel Of Patient-Derived Orthotopic Xenograft Mouse Models., Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank K Braun, Mari Kogiso, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Santosh Kesari, Steven Neuhauser, Timothy M Stearns, Jeffrey Chuang, Emily L Jocoy, Carol J Bult, Beverly Teicher, Malcolm A Smith, Xiao-Nan Li

Faculty Research 2026

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined …

Targeting Pediatric Glioblastomas By Combining Olig2 Inhibitor Ct-179 With Fractionated Radiation In A Panel Of Patient-Derived Orthotopic Xenograft Mouse Models., Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank K Braun, Mari Kogiso, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Santosh Kesari, Steven Neuhauser, Timothy M Stearns, Jeffrey Chuang, Emily L Jocoy, Carol J Bult, Beverly Teicher, Malcolm A Smith, Xiao-Nan Li

Faculty Research 2026

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined …

Development Of An Aav-Based Gene Therapy For The Ocular Phenotype Of Friedreich's Ataxia., Heyu Tang, Siddhant Gupte, Emily Xu, Kaitlyn R Calabro, Hannah Friend, Sean M Crosson, Diego Fajardo, Zachary Kostamo, Hangning Zhang, James J Peterson, Fangyu Lin, Zbynek Kozmik, Cathleen Lutz, Sanford L Boye, Shannon E Boye

Faculty Research 2026

Friedreich's ataxia (FA) is a leading form of hereditary ataxia caused by autosomal recessive mutations in frataxin (FXN). GAA triplet repeat expansions lead to lower levels of FXN expression, abnormal influx of iron into mitochondria, and damage to the nervous system. Patients typically present before the second decade with loss of muscular function, speech impediments, and cardiomyopathy. At later stages, vision loss typically manifests. Work is under way to develop gene therapies that address the cardiac and CNS manifestations, but their routes of administration do not lead to efficient transduction of the retina. The purpose of this study was to …

Ubiquitination Of Oncogenic Mutant P53 Via Attenuation Of Ribosome Biogenesis Machinery Effectively Inhibits Pancreatic Tumor Growth, Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

Faculty, Staff and Student Publications

Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA …

Repurposing Of The Macrolide Antibiotic Clarithromycin For The Prevention Of Lung Cancer, Shanshan Deng, Tabish Hussain, Thais F Bartelli, Manu M Sebastian, Melody Zarghooni, Walter V Velasco, Brandon Somerville, Linda Phan, Michelle I Savage, Yurong Song, John L Clifford, Humam Kadara, Florencia Mcallister, Powel H Brown, Seyed Javad Moghaddam, C Marcelo Aldaz

Faculty, Staff and Student Publications

Drug repurposing is the process of reusing existing pharmaceuticals for novel clinical purposes, which offers advantages such as streamlined clinical trial access and reduced drug development costs. Clarithromycin (CAM), a member of the macrolide antibiotics family, is a promising candidate for repurposing in cancer therapy due to its known preclinical and clinical immunomodulatory and anticancer properties. In the current study, we investigated whether CAM could be repurposed as a preventive treatment for KRAS-mutant lung cancer, a subtype of lung adenocarcinoma that is strongly associated with heavy smoking. CCSPCre; LSL-KrasG12D mice at an early stage of tumor development were treated with …

Rev-Erb-Alpha And -Beta Coordinately Regulate Astrocyte Reactivity And Proteostatic Function, Collin J Nadarajah, Michelle Y Li, Elsa I Quillin, Kevin Boyer, Julie M Dimitry, Yining Chen, Melvin W King, Ibrahim O Saliu, Jiyeon Lee, Patrick W Sheehan, Albert A Davis, Mitchell A Lazar, Guoyan Zhao, Erik S Musiek

2020-Current year OA Pubs

The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (

Immunogenicity And Efficacy Of A Rabies-Based Vaccine Against Highly Pathogenic Influenza H5n1 Virus, Nir Paran, Christoph Wirblich, Randy Albrecht, Leila Zabihi Diba, Alessandro Tarquinio, Drishya Kurup, Charalambos C. Solomides, Adolfo García-Sastre, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

The recent spillover of highly pathogenic influenza A/H5N1 (HPAI-H5N1) viruses to cattle, other mammals, and humans poses a major risk to animal and human health. Virus adaptation to new species highlights the need for effective vaccines for animals and humans. We recently developed a rabies virus-based H5 vaccine encoding the HPAI-H5 antigen and presenting it on the surface of the rabies virus particle. To test the immunogenicity and efficacy of the vaccine in eliciting systemic and mucosal immune response, we vaccinated mice intramuscularly or intranasally with either live or inactivated and adjuvanted vaccine. The vaccine elicited neutralizing antibodies against RABV …

Slc7a8 Is Essential For Metabolic Fitness And Function Of Th2 Cells, Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Shitong Wu, Patrick Fernandes Rodrigues, Raki Sudan, Yizhou Liu, Haerin Jung, Intelly Lee, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna

2020-Current year OA Pubs

Amino acids are essential for the activation and function of CD4 T helper (Th) cells, which differentiate into Th1, Th2, Th17, and Treg subsets to coordinate immune responses. While specific amino acid transporters have been identified for Th1, Th17, and Tregs, a transporter regulating Th2 cells remains unknown. This study identifies SLC7A8 as a Th2-specific amino acid transporter in the Th compartment. We found that Slc7a8 expression is upregulated in Th2 cells compared with other T helper subsets, and Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production. Furthermore, SLC7A8 was found to be crucial for an effective type 2 …

Amyloidosis Of Bridging Veins Is A Pathologic Feature Of Alzheimer's Disease, Leon C D Smyth, Daan Verhaege, Elio Standen-Bloom, Yue Wu, Steffen E Storck, Pavle Boskovic, Benjamin A Plog, Tornike Mamuladze, Jose A Mazzitelli, Zhuoying Wang, Daniel D Lee, Gwendalyn J Randolph, Katherine E Schwetye, Song Hu, Jonathan Kipnis, Et Al.

2020-Current year OA Pubs

Alzheimer's disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance …

Osimertinib Activates A Tgf-Β2-Dependent Secretory Program That Drives Lung Adenocarcinoma Progression, Madhurima Ghosh, Chao Wu, Abhishek Kumar, Monique Nilsson, John V Heymach, Weina Zhao, Jiang Yu, Xin Liu, Na Ding, Shike Wang, Guan-Yu Xiao, Angelo Chen, Kate Grimley, William K Russell, Chad J Creighton, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist osimertinib (Osi) eventually relapse, owing in part to the emergence of drug-tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intratumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell …

Nrn1 As A Therapeutic Target For Alzheimer's Disease., Derian A Pugh, Gregory Cary, Kelsey M Greathouse, Lauren C Nassour-Caswell, Emma L Hobby, Nicholas T Seyfried, Jeremy H Herskowitz

Faculty Research 2026

INTRODUCTION: Neuritin-1 (NRN1) was identified as a synaptic protein associated with cognitive resilience to Alzheimer's disease (AD).

METHODS: Target risk score and cell type expression profiles were generated for NRN1 using methods developed by the Emory-Sage-SGC-JAX Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Antibody characterization was conducted using Western blots and densitometry to assess the relative protein abundances of NRN1 in rodents, humans, and cell models.

RESULTS: NRN1 has a TREAT-AD target risk score of 3.29 out of 5. Based on single-nucleus RNA sequencing from SEA-AD, NRN1 expression …

Nrn1 As A Therapeutic Target For Alzheimer's Disease., Derian A Pugh, Gregory Cary, Kelsey M Greathouse, Lauren C Nassour-Caswell, Emma L Hobby, Nicholas T Seyfried, Jeremy H Herskowitz

Faculty Research 2026

INTRODUCTION: Neuritin-1 (NRN1) was identified as a synaptic protein associated with cognitive resilience to Alzheimer's disease (AD).

METHODS: Target risk score and cell type expression profiles were generated for NRN1 using methods developed by the Emory-Sage-SGC-JAX Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Antibody characterization was conducted using Western blots and densitometry to assess the relative protein abundances of NRN1 in rodents, humans, and cell models.

RESULTS: NRN1 has a TREAT-AD target risk score of 3.29 out of 5. Based on single-nucleus RNA sequencing from SEA-AD, NRN1 expression …

Somatic Deficiency Of The Human E3 Ubiquitin Ligase Cbl In Leukocytes Impairs B Cell But Not T Cell Development And Function., Taja Vatovec, Anna-Lena Neehus, Katherine J L Jackson, Danielle T Avery, Ivan Bagarić, Lucia Erazo, Carlos A Arango-Franco, Masato Ogishi, Syed F Ahmed, Axel Cederholm, Amanda J Russell, Erika Della Mina, Dena Al-Rifai, Rowena Bull, Lori Buetow, Steicy Sobrino, Allison Zhang, Lara Wahlster, Marine Michelet, Nima Parvaneh, Jessica Peel, Federica Barzaghi, Davide Leardini, Quentin Philippot, Francesco Saettini, Jacques Dutrieux, Benedicte De Muylder, Francesca Vendemini, Francesco Baccelli, Albert Catala, Eleonora Gambineri, Marinella Veltroni, Vignesh Pandiarajan, Yurena Aguilar, Filomeen Haerynck, Michael Elliott, Stuart Turville, Fabienne Brillot, Taushif Khan, Filippo Consonni, Laureline Berteloot, William A Sewell, Geetha Rao, Laetitia Largeaud, Francesca Conti, Cecile Roullion, Cécile Masson, Francesco Pegoraro, Tianyi Ye, Samantha Joubran, Emily Villalpando, Boris Bessot, Yoann Seeleuthner, Tom Le Voyer, Jérémie Rosain, Hailun Li, Zarah Janda, Edoardo Muratore, Camille Soudée, Eric Delabesse, Claire Goulvestre, Mohammad Shahrooei, Anne Puel, Isabelle André, Christine Bole-Feysot, Laurent Abel, Miriam Erlacher, Vivien Béziat, Chantal Lagresle-Peyrou, Remi Cheynier, Emmanuelle Six, Nico Marr, Marlène Pasquet, Laia Alsina, Christopher C Goodnow, Nils Landegren, Alessandro Aiuti, Peng Zhang, Riccardo Masetti, Danny T Huang, Cindy S Ma, Jean-Laurent Casanova, Vijay G Sankaran, Jacinta Bustamante, Stuart G Tangye, Jonathan Bohlen

Faculty Research 2026

The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis …

Divergent Humoral Immune Signatures In Response To Klebsiella Pneumoniae Bacteremia, Paeton L Wantuch, Nadia Wattad, David A Rosen

2020-Current year OA Pubs

OBJECTIVES: Klebsiella pneumoniae is an increasingly threatening global pathogen with high rates of antibiotic resistance and no licensed vaccines available. Despite its worldwide importance, little is known about the human adaptive immune response to K. pneumoniae infection.

METHODS: Herein we observed the longitudinal antibody responses of three immunocompetent patients hospitalized with K. pneumoniae bacteremia. We analyzed the human serum for antibody titers and in vitro functionality. Further, serum function was evaluated via an in vivo mouse model.

RESULTS: We found that in each case, anti-K. pneumoniae antibodies against the infecting strain were still detectable a year after the initial infection. …

Accelerated Diffusion Basis Spectrum Imaging With Tensor Computations, Kainen L Utt, Jacob S Blum, Donsub Rim, Sheng-Kwei Song

2020-Current year OA Pubs

This paper introduces an advanced framework for accelerated processing of diffusion-weighted imaging (DWI) data that utilizes an entire-image modeling approach to optimize the estimation of diffusion parameters from DWIs by mapping input diffusion data to predicted signals and estimating parameter values via a stochastic gradient descent optimizer (Adam). To validate this approach, we applied this framework to diffusion basis spectrum imaging (DBSI) and analyzed in vivo human brain and ex vivo mouse brain DWIs. Results demonstrate significant improvements to computational speed and signal-to-noise ratio (SNR) in estimated parameter maps compared to standard DBSI. Our approach is applicable to any diffusion …

Presenilin L166p Mutation, A Model Of Familial Alzheimer's Disease, Leads To Early Onset Bone Loss, Vidyani Suryadevara, Connor J Krehbial, Anuradha K Valiya, Melinda Vang, Julian Balanta-Melo, Pierre P Eleniste, Sumana Posritong, Jung Min Hong, Katie Chester, Gabriel M Pagnotti, Teresita Bellido, Monte S Willis, Angela Bruzzaniti

Faculty, Staff and Student Publications

Accelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with …

Decellularized Extracellular Matrix Scaffolds To Engineer The Dormant Landscape Of Microscopic Colorectal Cancer Liver Metastasis, Sabrina N Vandenheuvel, Lucia L Nash, Abigail J Clevenger, Claudia A Collier, Oscar R Benavides, Sanjana Roy, Brinlee Goggans, Aelita Salikhova, Anvitha Tharakesh, Svasti Haricharan, Amber N Stratman, Scott Kopetz, Alex J Walsh, Shreya A Raghavan

Faculty, Staff and Student Publications

Recurrent liver-metastatic colorectal cancer contributes to high mortality. Recurrence occurs when dormant, microscopic residual disease survives initial treatment to escape dormancy. In their dormant, microscopic state within the liver, these metastatic lesions are undetectable by clinical diagnostic imaging until they form overt, chemoresistant metastases. Therefore, understanding the molecular mechanisms underlying dormancy in colorectal cancer liver metastases is a significant knowledge gap, motivating the engineering of nuanced in vitro models of disease. The current work presents an engineered model of liver-metastatic colorectal cancer dormancy. Decellularized extracellular matrix (dECM) scaffolds are used to provide microscopic colorectal cancer cell clusters with a biomimetic, …

Local Delivery Of Mir-27a* Using Ultrasound-Targeted Microbubble Cavitation Inhibits Squamous Cell Carcinoma Growth, Nikhil S Chari, Cheng Chen, Thiruganesh Ramasamy, Xucai Chen, Geetika Wadhwa, Anurag N Paranjape, Stephen Y Lai, Flordeliza S Villanueva

Faculty, Staff and Student Publications

Objective: Ultrasound-targeted microbubble (MB) cavitation (UTMC) is an image-guided therapeutic oligonucleotide delivery platform utilizing intravenously injected gas-filled ultrasound contrast agents, which carry the therapeutic on the MB shell. During transit of MBs in the microcirculation of target tissue, ultrasound causes MB oscillation, facilitating endocytosis-independent payload uptake within insonified cells. Here, we tested the hypothesis that UTMC-mediated miR-27a* delivery will reduce tumor growth rate and result in accumulation of miR-27a* within tumor cells and the tumor microenvironment.

Methods: We used UTMC to deliver miR-27a* to SCC-VII cells in vitro and in SCC-VII mouse tumor models. Pulsed ultrasound was delivered during intravenous …

Investigating The Oxygen Dependence Of Flash-Rt Using Electron Paramagnetic Resonance Imaging, Trey Waldrop, Grace Murley, Brett Velasquez, Elise Konradsson, Denae Neill, Luke Connell, Alan Lopez Hernandez, Abagail Delahoussaye, F William Schuler, Jorge De La Cerda, Ziyi Li, Mark D Pagel, Emil Schüler

Faculty, Staff and Student Publications

Purpose: The FLASH effect occurs when radiation given at ultra-high dose rates spares healthy tissue while achieving isoeffective tumor control relative to conventional (CONV) dose rate irradiation. Limited data has implicated oxygen in the FLASH effect. This study investigated the effect of tissue oxygen tension (pO2) on gastrointestinal (GI) FLASH sparing in mice.

Methods: pO2 was quantified in vivo by electron paramagnetic resonance imaging (EPRI)- noninvasive oximetry through spin probe injection and magnetic resonance co-registration- and a phosphorescent quenching microsensor. B6(Cg)-Tyrc-2 J/J female mice were imaged while breathing 10%, 21%, and 95% oxygen. C57BL/6 mice of both sexes underwent microsensor …

Tbr2-Dependent Parallel Pathways Regulate The Development Of Distinct Iprgc Subtypes, Takae Kiyama, Ching-Kang Chen, Halit Y Altay, Yu-Jiun Chen, Leviette Sigala, Dan Su, Steven Eliason, Brad A Amendt, Chai-An Mao

Faculty, Staff and Student Publications

The intrinsically photosensitive retinal ganglion cells (ipRGC) are the conduit between the retina and brain regions responsible for non-image-forming and image-forming vision. In mice, six ipRGC subtypes have been discovered based on morphological characteristics, functions, and molecular profiles. All ipRGCs arise from Tbr2-expressing RGCs during developmental stages and subsequently diverge and differentiate into the six mature, distinct subtypes in adult retinas. However, the cellular and molecular mechanisms controlling the formation and maturation of the six ipRGC subtypes remain elusive. Here, we demonstrate that two Tbr2-dependent transcription factors, Iroquois‑related homeobox 1 (Irx1) and T-box containing factor 20 (Tbx20), are key downstream …

Neurological Recovery After Ich Is Mediated By The Aryl Hydrocarbon Receptor-Bilirubin Interplay Through Improved Erythrophagocytosis, Xiurong Zhao, Shun-Ming Ting, Guanghua Sun, Jaroslaw Aronowski

Faculty, Staff and Student Publications

Hematoma clearance after ICH is a pro-hemostatic process aiming at repair/recovery and is achieved through microglia/macrophages (MMΦ)-mediated erythrophagocytosis. Upon the engulfment of masses of erythrocytes and toxic hemolysis products, hemoglobin and heme, phagocytes convert them to bilirubin (BrB). Bilirubin is essentially not soluble in water and when overproduced, it precipitates within the cell causing injury. Thus, keeping bilirubin soluble and at a low intracellular level is needed for proper function of MMΦ. Here, using cultured microglia (MG), we found that intracellular formation of BrB in microglia during erythrophagocytosis coincides with the activation of transcription factor AhR, and AhR target genes …

Age-Independent Anti-Angiogenic Therapy For Choroidal Neovascularization By Targeting Secretogranin Iii, Chengchi Huang, Hong Tian, Wei Li

Faculty, Staff and Students Publications

Recent studies reported that anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) alleviate choroidal neovascularization (CNV) in young but not aged animals. We recently developed a disease-targeted anti-angiogenic therapy against secretogranin III (Scg3), which selectively binds to diseased but not healthy vessels in young mice. Herein, using a unique in vivo ligand binding assay, we predicted and confirmed that Scg3 selectively binds CNV vessels in both young and aged mice. In contrast, VEGF with minimal increased binding to CNV vessels exhibited an age-dependent decline in binding to both CNV and healthy vessels with negligible binding in aged mice. Based on …

Induction Of Yin Yang 1 (Yy1) Overexpression In Mature Adipocytes Promotes Dysfunctional Adipose Tissue And Systemic Insulin Resistance In Mice, Line Pedersen, Christy M Gliniak, Thomas Myhre Dale, Qingzhang Zhu, Chao Li, Jan-Bernd Funcke, Clair Crewe, Jiahui Luo, Lauren Palluth, Yi Zhu, Philipp E Scherer

Faculty, Staff and Students Publications

The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced …

A Scalable Organoid Model Of Urothelial Aging For Metabolic Interrogation, Infection Modeling, And Reversal Of Age-Associated Changes, Adwaita R Parab, Arnold M Salazar, Steven J Bark, Margarita Divenko, Vasanta Putluri, D'Feau J Lieu, Aadya S Singh, Nagireddy Putluri, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also …

Bet Inhibitor-Based Combinations Targeting Novel Dependencies In Mecom-Rearranged (R) Aml, Christine E Birdwell, Warren Fiskus, Christopher P Mill, Tapan M Kadia, Naval Daver, Courtney D Dinardo, Koji Sasaki, John A Davis, Kaberi Das, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B Flores, Rasoul Pourebrahim, Selina Yuan, Xiaoping Su, Michele Ceribelli, Kapil N Bhalla

Faculty, Staff and Student Publications

MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry …

A Systemic Selective Modified Mrna Delivery Platform For Preventing Chemotherapy-Induced Cardiotoxicity, Jimeen Yoo, Mengcheng Shen, Et Al.

2020-Current year OA Pubs

Doxorubicin (Dox) is a widely employed chemotherapeutic agent, but its use is clinically limited by dose-accumulative cardiotoxicity. More specifically, Dox induces oxidative stress and causes pro-apoptotic ceramide accumulation in cardiomyocytes (CMs). Acid ceramidase (AC) modified mRNA (modRNA) has been shown to reduce ceramide levels and protect the heart following ischemic injury; however, therapeutic modRNA applications have been hindered by the need for invasive delivery. Here, we present a platform for minimally intrusive transmission of modRNA to the heart. This CM-selective modRNA translational system (cmSMRTs) is encapsulated in lipid nanoparticles for intravenous (IV) delivery to enable systemic administration with high cardiac …

Progressive Neuroinflammation And Deficits In Motor Function In A Mouse Model With An Epg5 Pathogenic Variant Of Vici Syndrome., Bradley Thornton, Alexandra G. Hardinger, Laramie Pence, Priyanka Prem Kumar, Nikolas Connolly, Scott J. Weir, Jay L. Vivian

Manuscripts, Articles, Book Chapters and Other Papers

Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immune deficits, cardiomyopathy and progressive motor dysfunction. This devastating condition is caused by pathogenic variants in the EPG5 gene, which encodes a regulator of autophagy, leading to the accumulation of toxic intracellular material and widespread cellular dysfunction. Less-severe EPG5 pathogenic variants have recently been linked to rare familial forms of Parkinson's disease, suggesting deficits in EPG5 function drive a range of neurodegenerative disorders. Currently, there are no effective treatments for any disorders associated with pathogenic variants of EPG5. The underlying cellular mechanisms driving the progressive …

Human Chorionic Gonadotropin Decreases Cerebral Cystic Encephalomalacia And Parvalbumin Interneuron Degeneration In A Pro-Inflammatory Model Of Mouse Neonatal Hypoxia-Ischemia, Benjamin Miller, Alexander Crider, Bhooma Aravamuthan, Rafael Galindo

2020-Current year OA Pubs

Human chorionic gonadotropin (hCG) is an immunoregulatory and neurotrophic glycoprotein of potential clinical utility in the neonate at risk for cerebral injury. However, hCG has not been demonstrated to affect the pro-degenerative actions of inflammation in neonatal brain injury. Here we utilize a neonatal mouse model of mild hypoxia-ischemia (HI) combined with intraperitoneal administration of lipopolysaccharide (LPS) to evaluate the neuroprotective actions of hCG in the setting of systemic inflammation. Intraperitoneal treatment with hCG significantly decreased tissue loss and cystic degeneration in the hippocampus and cerebral cortex of term-equivalent neonatal mice exposed to LPS and HI. Noting that parvalbumin immunoreactive …

Sequential Platinum And Parp Inhibition Enhances Pd1 Immunotherapy Efficacy In Murine Brca2 Mutated Pancreatic Cancer, John C Mcvey, Max M Wattenberg, Heather Coho, Kayjana Infante, Kelly Markowitz, Devora Delman, Cynthia Clendenin, Emma E Furth, Rashmi Tondon, Ben Z Stanger, Robert H Vonderheide, Kim A Reiss, Gregory L Beatty

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA-mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA-mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, …