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Which Mouse Multiparental Population Is Right For Your Study? The Collaborative Cross Inbred Strains, Their F1 Hybrids, Or The Diversity Outbred Population., Gregory R Keele

Faculty Research 2023

Multiparental populations (MPPs) encompass greater genetic diversity than traditional experimental crosses of two inbred strains, enabling broader surveys of genetic variation underlying complex traits. Two such mouse MPPs are the Collaborative Cross (CC) inbred panel and the Diversity Outbred (DO) population, which are descended from the same eight inbred strains. Additionally, the F1 intercrosses of CC strains (CC-RIX) have been used and enable study designs with replicate outbred mice. Genetic analyses commonly used by researchers to investigate complex traits in these populations include characterizing how heritable a trait is, i.e. its heritability, and mapping its underlying genetic loci, i.e. its …

Foxi3 Pathogenic Variants Cause One Form Of Craniofacial Microsomia, Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro De Luca, Giuseppe Merla, Shouqin Zhao, Timothy C Cox, Andrew K Groves, James R Lupski, Qingguo Zhang, Yong-Biao Zhang, Stylianos E Antonarakis

Faculty, Staff and Students Publications

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in …

Sting-Dependent Interferon Signatures Restrict Osteoclast Differentiation And Bone Loss In Mice, Susan Maclauchlan, Priyanka Kushwaha, Albert Tai, Sijia Chen, Catherine Manning, Gaurav Swarnkar, Yousef Abu-Amer, Katherine A Fitzgerald, Shruti Sharma, Ellen M Gravallese

2020-Current year OA Pubs

Stimulator of interferon genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed that ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFNβ and IFN-I interferon-stimulated genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to receptor activator of NF-kappaB ligand (RANKL) in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation …

Uropathogenic Escherichia Coli Infection-Induced Epithelial Trained Immunity Impacts Urinary Tract Disease Outcome, Seongmi K Russell, Jessica K Harrison, Benjamin S Olson, Hyung Joo Lee, Valerie P O'Brien, Xiaoyun Xing, Lu Yu, Elisha D O Roberson, Rajdeep Bomjan, Changxu Fan, Marina Sha, Marco Colonna, Ting Wang, Thomas J Hannan, Scott J Hultgren, Et Al.

2020-Current year OA Pubs

Previous urinary tract infections (UTIs) can predispose one to future infections; however, the underlying mechanisms affecting recurrence are poorly understood. We previously found that UTIs in mice cause differential bladder epithelial (urothelial) remodelling, depending on disease outcome, that impacts susceptibility to recurrent UTI. Here we compared urothelial stem cell (USC) lines isolated from mice with a history of either resolved or chronic uropathogenic Escherichia coli (UPEC) infection, elucidating evidence of molecular imprinting that involved epigenetic changes, including differences in chromatin accessibility, DNA methylation and histone modification. Epigenetic marks in USCs from chronically infected mice enhanced caspase-1-mediated cell death upon UPEC …

Mapping The Metabolic Reprogramming Induced By Sodium-Glucose Cotransporter 2 Inhibition, Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz

Faculty, Staff and Student Publications

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation …

Targeting The Mevalonate Pathway Suppresses Arid1a-Inactivated Cancers By Promoting Pyroptosis, Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R Goldman, Toshitha Kannan, Andrew V Kossenkov, Ronny Drapkin, Luis J Montaner, Daniel T Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Faculty, Staff and Student Publications

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC …

Neuronal Birthdate Reveals Topography In A Vestibular Brainstem Circuit For Gaze Stabilization, Dena Goldblatt, Stephanie Huang, Marie R Greaney, Kyla R Hamling, Venkatakaushik Voleti, Citlali Perez-Campos, Kripa B Patel, Wenze Li, Elizabeth M C Hillman, Martha W Bagnall, David Schoppik

Faculty, Staff and Student Publications

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. …

Neuronal Birthdate Reveals Topography In A Vestibular Brainstem Circuit For Gaze Stabilization, Dena Goldblatt, Stephanie Huang, Marie R Greaney, Kyla R Hamling, Venkatakaushik Voleti, Citlali Perez-Campos, Kripa B Patel, Wenze Li, Elizabeth M C Hillman, Martha W Bagnall, David Schoppik

2020-Current year OA Pubs

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. …

Il-15 Enhances Hiv-1 Infection By Promoting Survival And Proliferation Of Ccr5+Cd4+ T Cells, Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan

2020-Current year OA Pubs

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4+ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5+CD4+ T cells, drove their expansion, …

Disruptive Lysosomal-Metabolic Signaling And Neurodevelopmental Deficits That Precede Purkinje Cell Loss In A Mouse Model Of Niemann-Pick Type-C Disease., Sarah Kim, Kathleen Ochoa, Sierra E Melli, Fawad A K Yousufzai, Zerian D Barrera, Aela A Williams, Gianna Mcintyre, Esteban Delgado, James N Bolish, Collin M Macleod, Mary Boghos, Hayden P Lens, Alex G Ramos, Vincent B Wilson, Kelly Maloney, Zachary M Padron, Amaal H Khan, Rosa E Blanco, Ileana Soto

College of Science & Mathematics Departmental Research

Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1nmf164 mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1nmf164 PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed …

Translation Of Immunomodulatory Therapy To Treat Chronic Heart Failure: Preclinical Studies To First In Human, H. David Humes, Keith D. Aaronson, Deborah A. Buffington, Hani N. Sabbah, Angela J. Westover, Lenar T. Yessayan, Balazs Szamosfalvi, Francis D. Pagani

Cardiology Articles

BACKGROUND: Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system.

AIM: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF.

METHODS AND RESULTS: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished …

Bi-Allelic Variants In The Esam Tight-Junction Gene Cause A Neurodevelopmental Disorder Associated With Fetal Intracranial Hemorrhage, Mauro Lecca, Davut Pehlivan, Damià Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarella, Alberto Neri, Carlo Fusco, Dana Marafi, Tadahiro Mitani, Jennifer Ellen Posey, Sadik Etka Bayramoglu, Alper Gezdirici, Jessica Hernandez-Rodriguez, Emilia Amengual Cladera, Elena Miravet, Jorge Roldan-Busto, María Angeles Ruiz, Cristofol Vives Bauzá, Liat Ben-Sira, Sabine Sigaudy, Anaïs Begemann, Sheila Unger, Serdal Güngör, Semra Hiz, Ece Sonmezler, Yoav Zehavi, Michael Jerdev, Alessandra Balduini, Orsetta Zuffardi, Rita Horvath, Hanns Lochmüller, Anita Rauch, Livia Garavelli, Elisabeth Tournier-Lasserve, Ronen Spiegel, James R Lupski, Edoardo Errichiello

Faculty, Staff and Students Publications

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in …

Sphingomyelin 16:0 Is A Therapeutic Target For Neuronal Death In Acid Sphingomyelinase Deficiency, Ángel Gaudioso, Xuntian Jiang, Josefina Casas, Edward H Schuchman, María Dolores Ledesma

2020-Current year OA Pubs

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of …

The Impact Of Gamma Transcranial Alternating Current Stimulation (Tacs) On Cognitive And Memory Processes In Patients With Mild Cognitive Impairment Or Alzheimer’S Disease: A Literature Review, N.R. Nissim, D.V.H. Pham, T. Poddar, E. Blutt, R.H. Hamilton

Moss-Magee Rehabilitation Papers

BACKGROUND: Transcranial alternating current stimulation (tACS)-a noninvasive brain stimulation technique that modulates cortical oscillations through entrainment-has been demonstrated to alter oscillatory activity and enhance cognition in healthy adults. TACS is being explored as a tool to improve cognition and memory in patient populations with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

OBJECTIVE: To review the growing body of literature and current findings obtained from the application of tACS in patients with MCI or AD, highlighting the effects of gamma tACS on brain function, memory, and cognition. Evidence on the use of brain stimulation in animal models of AD is …

Differential Splicing Of Neuronal Genes In A Trem2*R47h Mouse Model Mimics Alterations Associated With Alzheimer's Disease., Ravi S Pandey, Kevin P Kotredes, Michael Sasner, Gareth R Howell, Gregory W. Carter

Faculty Research 2023

BACKGROUND: Molecular characterization of late-onset Alzheimer's disease (LOAD), the leading cause of age-related dementia, has revealed transcripts, proteins, and pathway alterations associated with disease. Assessing these postmortem signatures of LOAD in experimental model systems can further elucidate their relevance to disease origins and progression. Model organisms engineered with human genetic factors further link these signatures to disease-associated variants, especially when studies are designed to leverage homology across species. Here we assess differential gene splicing patterns in aging mouse models carrying humanized APOE4 and/or the Trem2*R47H variant on a C57BL/6J background. We performed a differential expression of gene (DEG) and differential …

Pattern Dynamics And Stochasticity Of The Brain Rhythms, Clarissa Hoffman, Jingheng Cheng, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves—their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses “orderliness” of the waves’ features. The corresponding measures capture the waves’ characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns’ dynamics and the animal’s location, speed, and acceleration. Specifically, we …

Statins Enhance The Efficacy Of Her2-Targeting Radioligand Therapy In Drug-Resistant Gastric Cancers, Yi Rao, Zachary Samuels, Lukas M Carter, Sebastien Monette, Sandeep Surendra Panikar, Patricia M R Pereira, Jason S Lewis

2020-Current year OA Pubs

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous …

Pattern Dynamics And Stochasticity Of The Brain Rhythms, Clarissa Hoffman, Jingheng Cheng, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Student Publications

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves-their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses "orderliness" of the waves' features. The corresponding measures capture the waves' characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns' dynamics and the animal's location, speed, and acceleration. Specifically, we …

Cd73-Dependent Adenosine Signaling Through Adora2b Drives Immunosuppression In Ductal Pancreatic Cancer, Erika Y Faraoni, Kanchan Singh, Vidhi Chandra, Olivereen Le Roux, Yulin Dai, Ismet Sahin, Baylee J O'Brien, Lincoln N Strickland, Le Li, Emily Vucic, Amanda N Warner, Melissa Pruski, Trent Clark, George Van Buren, Nirav C Thosani, John S Bynon, Curtis J Wray, Dafna Bar-Sagi, Kyle L Poulsen, Lana A Vornik, Michelle I Savage, Shizuko Sei, Altaf Mohammed, Zhongming Zhao, Powel H Brown, Tingting Mills, Holger K Eltzschig, Florencia Mcallister, Jennifer M Bailey-Lundberg

Faculty, Staff and Student Publications

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. …

Swi/Snf Blockade Disrupts Pu1-Directed Enhancer Programs In Normal Hematopoietic Cells And Acute Myeloid Leukemia, Courtney Chambers, Katerina Cermakova, Yuen San Chan, Kristen Kurtz, Katharina Wohlan, Andrew Henry Lewis, Christiana Wang, Anh Pham, Milan Dejmek, Michal Sala, Mario Loeza Cabrera, Rogelio Aguilar, Radim Nencka, H Daniel Lacorazza, Rachel E Rau, H Courtney Hodges

Faculty, Staff and Students Publications

UNLABELLED: In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition …

Il6 Mediates Suppression Of T- And Nk-Cell Function In Emt-Associated Tki-Resistant Egfr-Mutant Nsclc, Sonia A Patel, Monique B Nilsson, Yan Yang, Xiuning Le, Hai T Tran, Yasir Y Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L Gibbons, John V Heymach

Faculty, Staff and Student Publications

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype.

Experimental design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and …

Inhibition Of Stat6 With Antisense Oligonucleotides Enhances The Systemic Antitumor Effects Of Radiotherapy And Anti-Pd-1 In Metastatic Non-Small Cell Lung Cancer, Kewen He, Hampartsoum B Barsoumian, Nahum Puebla-Osorio, Yun Hu, Duygu Sezen, Mark D Wasley, Genevieve Bertolet, Jie Zhang, Carola Leuschner, Liangpeng Yang, Claudia S Kettlun Leyton, Natalie Wall Fowlkes, Morgan Maureen Green, Lisa Hettrick, Dawei Chen, Fatemeh Masrorpour, Meidi Gu, Hadi Maazi, Alexey S Revenko, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung …

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 …

Monocyte Depletion Enhances Neutrophil Influx And Proneural To Mesenchymal Transition In Glioblastoma, Zhihong Chen, David H Gutmann, Et Al.

2020-Current year OA Pubs

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no …

Dysregulation And Epigenetic Reprogramming Of Nrf2 Signaling Axis Promote Acquisition Of Cisplatin Resistance And Metastasis In Head And Neck Squamous Cell Carcinoma, Abdullah A Osman, Emre Arslan, Mason Bartels, Chieko Michikawa, Antje Lindemann, Katarzyna Tomczak, Wangjie Yu, Vlad Sandulache, Wencai Ma, Li Shen, Jing Wang, Anand K Singh, Mitchell J Frederick, Nakia D Spencer, Jeffery Kovacs, Timothy Heffernan, William F Symmans, Kunal Rai, Jeffrey N Myers

Faculty, Staff and Student Publications

PURPOSE: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.

EXPERIMENTAL DESIGN: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 …

Age-Related Changes To Adipose Tissue And Peripheral Neuropathy In Genetically Diverse Het3 Mice Differ By Sex And Are Not Mitigated By Rapamycin Longevity Treatment., Jake W Willows, Morganne Robinson, Zahra Alshahal, Samantha K Morrison, Gargi Mishra, Harrison Cyr, Magdalena Blaszkiewicz, Gilian Gunsch, Sabrina Dipietro, Emma Paradie, Benjamin Tero, Anne Harrington, Larisa Ryzhova, Lucy Liaw, Peter C. Reifsnyder, David E Harrison, Kristy L Townsend

Faculty Research 2023

Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased ('adipose neuropathy'). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose-resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the …

The Mouse Models Of Human Cancer Database (Mmhcdb)., Dale A. Begley, Debra M Krupke, John P Sundberg, Emily L Jocoy, Joel E Richardson, Steven Neuhauser, Carol J Bult

Faculty Research 2023

The laboratory mouse has served for decades as an informative animal model system for investigating the genetic and genomic basis of cancer in humans. Although thousands of mouse models have been generated, compiling and aggregating relevant data and knowledge about these models is hampered by a general lack of compliance, in the published literature, with nomenclature and annotation standards for genes, alleles, mouse strains and cancer types. The Mouse Models of Human Cancer database (MMHCdb) is an expertly curated, comprehensive knowledgebase of diverse types of mouse models of human cancer, including inbred mouse strains, genetically engineered mouse models, patient-derived xenografts, …

Developmental Changes In Electrophysiological Properties Of Auditory Cortical Neurons In The Cntnap2 Knockout Rat, Rajkamalpreet S Mann, Brian L Allman, Susanne Schmid

Anatomy and Cell Biology Publications

Disruptions in the CNTNAP2 gene are known to cause language impairments and symptoms associated with autism spectrum disorder (ASD). Importantly, knocking out this gene in rodents results in ASD-like symptoms that include auditory processing deficits. This study used in vitro patch-clamp electrophysiology to examine developmental alterations in auditory cortex pyramidal neurons of Cntnap2^-/- rats, hypothesizing that CNTNAP2 is essential for maintaining intrinsic neuronal properties and synaptic wiring in the developing auditory cortex. Whole cell patch-clamp recordings were conducted in wildtype and Cntnap2^-/- littermates at three postnatal age ranges (P8-12, P18-21, and …

Transcriptional Activation Of Jun And Fos Members Of The Ap-1 Complex Is A Conserved Signature Of Immune Aging That Contributes To Inflammaging., Emin Onur Karakaslar, Neerja Katiyar, Muneer G. Hasham, Ahrim Youn, Siddhartha Sharma, Cheng-Han Chung, Radu Marches, Ron Korstanje, Jacques Banchereau, Duygu Ucar

Faculty Research 2023

Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J and short-lived NZO/HILtJ mouse strains by profiling transcriptomes and epigenomes of immune cells from peripheral blood and the spleen from young and old mice. Transcriptional activation of the AP-1 transcription factor complex, particularly Fos, Junb, and Jun genes, was the most significant and conserved aging signature across tissues and strains. ATAC-seq data analyses showed that the chromatin around these genes was more accessible with age and there were significantly more binding sites for these TFs with age …

Probenecid Slows Disease Progression In A Murine Model Of Autosomal Dominant Polycystic Kidney Disease, Sergey N. Arkhipov, D'Anna L. Potter, Regina F. Sultanova, Daria V. Ilatovskaya, Peter C. Harris, Tengis S. Pavlov

Hypertension and Vascular Research Articles

Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1(RC/RC) mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. …