Medicine and Health Sciences Commons^™

Non-Canonical Role Of Dna Mismatch Repair On Sensory Processing In Mice, Sadia N Rahman, Demetrios Neophytou, Siboney Oviedo-Gray, Bao Q Vuong, Hysell V Oviedo

2020-Current year OA Pubs

DNA repair mechanisms are essential for cellular development and function. In post-mitotic neurons, deficiencies in DNA damage response proteins can lead to severe neurodegenerative and neurodevelopmental disorders. One highly conserved factor involved in DNA repair is MutS Homolog 2 (Msh2), which is responsible for correcting base-base mismatches and insertion/deletion loops during cell proliferation. However, its role in mature neurons remains poorly understood. This study investigates the impact of Msh2 loss on sensory processing in mice. Using electrophysiological and molecular assays, we identifiedsignificant deficits in cortical and thalamic sound processing in Msh2

Sting-Induced Blood-Brain Barrier Opening Combined With Radiotherapy Potentiates Antitumor Response In A High-Grade Glioma Model, Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Kathleen Mccortney, Peng Zhang, Craig M Horbinski, Lara Leoni, Ryan J Avery, Rimas V Lukas, Timothy L Sita, David R Raleigh, Sean Sachdev, Roger Stupp, Maciej S Lesniak, David M Ashley, Daniele Procissi, Michael A Curran, Irina Balyasnikova, Amy B Heimberger

Faculty, Staff and Student Publications

Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect …

Sting Activation Induces Cytotoxic And Immune Responses In Meningiomas Via Inflammatory Cell Death Pathways, Mark W Youngblood, Alexander H Stegh, Et Al.

2020-Current year OA Pubs

Meningiomas are common tumors of the central nervous system that are typically treated with surgery or radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using integrated molecular approaches, here we show that this pathway is targetable in both neoplastic and immune populations within the meningioma microenvironment. Meningioma tumor cells exhibit promoter hypomethylation and increased chromatin accessibility of the STING genomic locus, associated with robust expression of this gene. Treatment of diverse patient meningiomas ex vivo with 8803 induces direct tumor cytotoxicity through inflammatory …

Targeting Oxalate Production By Combining Enzyme Inhibition And Proteolysis Activation: A Novel Therapeutic Approach For Primary Hyperoxaluria Type 1, Fabio Arias, Sumati Rohilla, Yudibeth Sixto-López, Koral S E Richard, Sandeep Das, Pilar Maria Luque-Navarro, Juan Luis Pacheco-García, Reethika Gade, M Peyton Mckinney, Dhananjay Kumar, Jemiah Maxie, W Rylan Corr, Nilesh Pandey, Harpreet Kaur, Jibin Ding, Lin Tan, Elisha Scott, Hyung Nam, Eyal Gottlieb, A Wayne Orr, Nirav Dhanesha, Arif Yurdagul, Angel L Pey, Francisco Franco-Montalbán, José A Gómez Vidal, Oren Rom, Mónica Díaz-Gavilán

Faculty, Staff and Student Publications

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase (AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase (GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate metabolism, have shown promise in reducing oxalate burden. However, recently approved siRNA therapies remain limited by high cost, unfavorable pharmacokinetics, and limited global accessibility. We report the development of compound 2, a dual GO/LDHA inhibitor (K i = 390 and 40 nM, respectively) that also promotes hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy was evaluated in Agxt –/– mice, both in primary …

Targeting The Lung Innate Pathways During Tuberculosis Can Improve Vaccine-Induced Protection Via Th17 Responses In Diversity Outbred Mice, Mushtaq Ahmed, Shibali Das, Bruce A Rosa, Javier Rangel Moreno, Deepak Kaushal, Makedonka Mitreva, Shabaana A Khader

2020-Current year OA Pubs

UNLABELLED: Tuberculosis (TB), caused by the bacterium

IMPORTANCE: Bacille Calmette Guerin (BCG) vaccination in genetically diverse outbred (DO) mice provides significant protection against

Myokine Sirpα Exacerbates Kidney Disease In Diabetes, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E Mitch, Sandhya S Thomas

Faculty, Staff and Students Publications

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced …

Phytic Acid (Insp6) Activates Hdac3 Epigenetic Axis To Maintain Intestinal Barrier Function, Sujan Chatterjee, Katherine Huang, Kayci Huff-Hardy, Richard Rood, Anas Gremida, Martin Gregory, Chien-Huan Chen, Parakkal Deepak, Et Al.

2020-Current year OA Pubs

HDAC inhibition shows promise in cancer treatment but pan-HDAC inhibitors cause gastrointestinal issues in 48% of patients. Understanding HDAC activation mechanisms is crucial to treating diverse diseases beyond cancer. Our study reveals that inositol polyphosphate multikinase (IPMK) and inositol hexakisphosphate (InsP

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Tieling Zhou, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

Ubiquitination-Directed Cytosolic Dna Degradation Governs Cgas-Sting-Mediated Immune Response To Dna Damage, Lei Li, Qi Ye, Jinlu Ma, Zixi Wang, Tianjie Liu, Mingming Lu, Haohan Xiang, Buyun Li, Shan Xu, Ke Wang, Yule Chen, Jiaqi Chen, Bohan Ma, Wenyue Huang, Mengjiao Cai, Nan Wu, Yanqiang Li, Jiale An, Chongming Jiang, Rui Ye, Jing Liu, Steven H Lin, Yang Gao, Jian Ma, Lei Li

Faculty, Staff and Student Publications

Activation of cGAS-STING signaling in cancer cells requires cytosolic DNA produced by intrinsic or treatment-induced DNA damage. However, clinical efforts to exploit this pathway to improve immunotherapy have yielded limited success, highlighting gaps in understanding the link between DNA damage and immunotherapy. Here, we identify ubiquitination-directed cytosolic DNA degradation as a critical determinant for cGAS-STING activation following DNA damage. Mechanistically, the cytosolic DNA exonuclease TREX1 is degraded by the E3 ubiquitin ligase SPOP but is reversely stabilized by the deubiquitinase USP7. Cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and impairing cGAS-STING-mediated immune activation. Notably, …

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

Therapeutic Reprogramming Of Tumour-Associated Macrophages In Pancreatic Cancer Using A Cytotoxic Ccr2-Targeted Nanotheranostic, Vikas Kumar Somani, Xiaohui Zhang, Timothy Hung-Po Chen, Ashenafi Bulle, Sapana Bansod, Lin Li, Yutong Geng, Liang-I Kang, Gyu Seong Heo, Hannah Luehmann, Yuena Zhang, Muhammad A Saeed, Kory J Lavine, David G Denardo, Russell K Pachynski, Yongjian Liu, Kian-Huat Lim

2020-Current year OA Pubs

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumour microenvironment (TME) dominated by inflammatory monocytes (IMs) and tumour-associated macrophages (TAMs), which restrict adaptive immunity and drive resistance to immune checkpoint blockade (ICB). Recruitment of CCR2⁺ IMs by tumour-derived CCL2 is a central mechanism underlying TAM accumulation. Conventional gemcitabine (GEM) and small-molecule CCR2 inhibitors provide limited benefit due to poor intratumoural delivery, transient target engagement, and compensatory myeloid recruitment. METHODS: We engineered a CCR2-targeted nanotheranostic by conjugating a CCR2-binding peptide (ECL1i) and GEM onto ultrasmall copper nanoclusters (CuNCs-ECL1i-GEM; C-E-G). Therapeutic efficacy and immune remodelling were evaluated using orthotopic subcutaneous and …

Sclerostin Deficiency Sensitizes White Adipocytes To Thermogenic Signals That Induce Beiging In Mice, Gillian M Choquette, Soohyun P Kim, Kevin J Wilkinson, Belen C Avelar, Sushrut Pathy, Zhu Li, Jasmine Wu, Susan Aja, Daniel L J Thorek, Michael J Wolfgang, Ryan C Riddle

2020-Current year OA Pubs

Maintenance of bone mass is coordinated with adipose tissue function through the secretion of hormones and endocrine factors that act on the opposing tissue. Sclerostin, a small glycoprotein produced by osteocytes embedded within the bone matrix, potently suppresses bone formation by antagonizing Wnt/β-catenin signaling while stimulating adipose tissue accumulation via the same mechanism of action. Since sclerostin-deficient mice develop pockets of multilocular adipocytes in subcutaneous adipose, we investigate the influence of sclerostin on thermogenic and β3-adrenergic stimuli-induced white adipose tissue beiging. Here, we report that Sost gene expression in bone and serum sclerostin levels are induced by β3-adrenergic agonists via …

Repurposing Of The Macrolide Antibiotic Clarithromycin For The Prevention Of Lung Cancer, Shanshan Deng, Tabish Hussain, Thais F Bartelli, Manu M Sebastian, Melody Zarghooni, Brandon Somerville, 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 …

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, Neeraj Chauhan, 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 …

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 (

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, Jiang Yu, 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 …

Induction Of Yin Yang 1 (Yy1) Overexpression In Mature Adipocytes Promotes Dysfunctional Adipose Tissue And Systemic Insulin Resistance In Mice, 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 …

Age-Independent Anti-Angiogenic Therapy For Choroidal Neovascularization By Targeting Secretogranin Iii

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 …

A Scalable Organoid Model Of Urothelial Aging For Metabolic Interrogation, Infection Modeling, And Reversal Of Age-Associated Changes, 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 …

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 …

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 …

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. …

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, Sumana Posritong, 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 …

Tbr2-Dependent Parallel Pathways Regulate The Development Of Distinct Iprgc Subtypes, Takae Kiyama, Ching-Kang Chen, Halit Y Altay, Yu-Jiun Chen, Leviette Sigala, Steven Eliason, 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 …

Investigating The Oxygen Dependence Of Flash-Rt Using Electron Paramagnetic Resonance Imaging, Trey Waldrop, Grace Murley, Brett Velasquez, Elise Konradsson, Denae Neill, Alan Lopez Hernandez, 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 …

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, Brinlee Goggans, 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, …

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 …

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, Stephen Y Lai

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 …