Medicine and Health Sciences Commons^™

The Ifitm5 Mutation In Osteogenesis Imperfecta Type V Is Associated With An Erk/Sox9-Dependent Osteoprogenitor Differentiation Defect, Ronit Marom, I-Wen Song, Emily C Busse, Megan E Washington, Ava S Berrier, Vittoria C Rossi, Laura Ortinau, Youngjae Jeong, Ming-Ming Jiang, Brian C Dawson, Mary Adeyeye, Carolina Leynes, Caressa D Lietman, Bridget M Stroup, Dominyka Batkovskyte, Mahim Jain, Yuqing Chen, Racel Cela, Alexis Castellon, Alyssa A Tran, Isabel Lorenzo, D Nicole Meyers, Shixia Huang, Alicia Turner, Vinitha Shenava, Maegen Wallace, Eric Orwoll, Dongsu Park, Catherine G Ambrose, Sandesh Cs Nagamani, Jason D Heaney, Brendan H Lee

Faculty, Staff and Students Publications

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with …

Maldi Imaging Mass Spectrometry Visualizes The Distribution Of Antidepressant Duloxetine And Its Major Metabolites In Mouse Brain, Liver, Kidney, And Spleen Tissues, Saleh M Khalil, Xuan Qin, John M Hakenjos, Jian Wang, Zhaoyong Hu, Xinli Liu, Jin Wang, Mirjana Maletic-Savatic, Kevin R Mackenzie, Martin M Matzuk, Feng Li

Faculty, Staff and Student Publications

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none …

Structural Characterization Of Ligand Binding And Ph-Specific Enzymatic Activity Of Mouse Acidic Mammalian Chitinase, Roberto Efraín Díaz, Andrew K Ecker, Galen J Correy, Pooja Asthana, Iris D Young, Bryan Faust, Michael C Thompson, Ian B Seiple, Steven Van Dyken, Richard M Locksley, James S Fraser

2020-Current year OA Pubs

Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across …

A Longitudinal Mri And Tspo Pet-Based Investigation Of Brain Region-Specific Neuroprotection By Diazepam Versus Midazolam Following Organophosphate-Induced Seizures, Brad A Hobson, Douglas J Rowland, Yimeng Dou, Naomi Saito, Zachary T Harmany, Donald A Bruun, Danielle J Harvey, Abhijit J Chaudhari, Joel R Garbow, Pamela J Lein

2020-Current year OA Pubs

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, …

Prevalence Of Anti-Myelin Oligodendrocyte Glycoprotein Antibodies Across Neuroinflammatory And Neurodegenerative Diseases, Ritu R Trivedi, Angela S Archambault, Clarice Pavlak, Matteo Gastaldi, Claudia Cantoni, Laura Ghezzi, Anne H Cross, Timothy M Miller, Gregory F Wu

2020-Current year OA Pubs

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in …

Scanless Two-Photon Voltage Imaging, Ruth R Sims, Imane Bendifallah, Christiane Grimm, Aysha S Mohamed Lafirdeen, Soledad Domínguez, Chung Yuen Chan, Xiaoyu Lu, Benoît C Forget, François St-Pierre, Eirini Papagiakoumou, Valentina Emiliani

Faculty, Staff and Students Publications

Two-photon voltage imaging has long been heralded as a transformative approach capable of answering many long-standing questions in modern neuroscience. However, exploiting its full potential requires the development of novel imaging approaches well suited to the photophysical properties of genetically encoded voltage indicators. We demonstrate that parallel excitation approaches developed for scanless two-photon photostimulation enable high-SNR two-photon voltage imaging. We use whole-cell patch-clamp electrophysiology to perform a thorough characterization of scanless two-photon voltage imaging using three parallel illumination approaches and lasers with different repetition rates and wavelengths. We demonstrate voltage recordings of high-frequency spike trains and sub-threshold depolarizations from neurons …

Through The Cat-Map Gateway: A Brief History Of Cataract Genetics, Alan Shiels

2020-Current year OA Pubs

Clouding of the transparent eye lens, or cataract(s), is a leading cause of visual impairment that requires surgical replacement with a synthetic intraocular lens to effectively restore clear vision. Most frequently, cataract is acquired with aging as a multifactorial or complex trait. Cataract may also be inherited as a classic Mendelian trait-often with an early or pediatric onset-with or without other ocular and/or systemic features. Since the early 1990s, over 85 genes and loci have been genetically associated with inherited and/or age-related forms of cataract. While many of these underlying genes-including those for lens crystallins, connexins, and transcription factors-recapitulate signature …

Structural Analysis Of The Female Reptile Reproductive System By Micro-Computed Tomography And Optical Coherence Tomography†, Bonnie K Kircher, Michaela A Mccown, Deirdre M Scully, Richard R Behringer, Irina V Larina

Faculty, Staff and Student Publications

Volumetric data provide unprecedented structural insight to the reproductive tract and add vital anatomical context to the relationships between organs. The morphology of the female reproductive tract in non-avian reptiles varies between species, corresponding to a broad range of reproductive modes and providing valuable insight to comparative investigations of reproductive anatomy. However, reproductive studies in reptilian models, such as the brown anole studied here, have historically relied on histological methods to understand the anatomy. While these methods are highly effective for characterizing the cell types present in each organ, histological methods lose the 3D relationships between images and leave the …

Machine Learning In Time-Lapse Imaging To Differentiate Embryos From Young Vs Old Mice†, Liubin Yang, Carolina Leynes, Ashley Pawelka, Isabel Lorenzo, Andrew Chou, Brendan Lee, Jason D Heaney

Faculty, Staff and Students Publications

Time-lapse microscopy for embryos is a non-invasive technology used to characterize early embryo development. This study employs time-lapse microscopy and machine learning to elucidate changes in embryonic growth kinetics with maternal aging. We analyzed morphokinetic parameters of embryos from young and aged C57BL6/NJ mice via continuous imaging. Our findings show that aged embryos accelerated through cleavage stages (from 5-cells) to morula compared to younger counterparts, with no significant differences observed in later stages of blastulation. Unsupervised machine learning identified two distinct clusters comprising of embryos from aged or young donors. Moreover, in supervised learning, the extreme gradient boosting algorithm successfully …

An Inducible Genetic Tool To Track And Manipulate Specific Microglial States Reveals Their Plasticity And Roles In Remyelination, Kia M Barclay, Nora Abduljawad, Zuolin Cheng, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A Mazzitelli, Leon C D Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, Jinchao Hou, Naresha Saligrama, Marco Colonna, Guoqiang Yu, Jonathan Kipnis, Qingyun Li

The Brown Foundation: Institute of Molecular Medicine

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative region-associated microglia (PAM) in developing white matter and disease-associated microglia (DAM) prevalent in various neurodegenerative conditions. PAM and DAM share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreERT2, that targets PAM and DAM in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several …

Frontotemporal Dementia-Like Disease Progression Elicited By Seeded Aggregation And Spread Of Fus, Sonia Vazquez-Sanchez, Britt Tilkin, Fatima Gasset-Rosa, Sitao Zhang, Diana Piol, Melissa Mcalonis-Downes, Jonathan Artates, Noe Govea-Perez, Yana Verresen, Lin Guo, Don Cleveland, James Shorter, Sandrine Da Cruz

Department of Biochemistry and Molecular Biology Faculty Papers

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation …

Tmprss2 Is A Tumor Suppressor And Its Downregulation Promotes Antitumor Immunity And Immunotherapy Response In Lung Adenocarcinoma, Zhixian Liu, Qiqi Lu, Zhilan Zhang, Qiushi Feng, Xiaosheng Wang

Faculty, Staff and Student Publications

Background: TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains insufficiently unexplored.

Methods: In five bulk transcriptomics datasets, one single-cell RNA sequencing (scRNA-seq) dataset and one proteomics dataset for lung adenocarcinoma (LUAD), we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, genomic features, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we performed experimental validation of the bioinformatics findings.

Results: TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios …

Role Of Ethanolamine Utilization And Bacterial Microcompartment Formation In Listeria Monocytogenes Intracellular Infection, Ayan Chatterjee, Karan Gautam Kaval, Danielle A Garsin

Faculty, Staff and Student Publications

Ethanolamine (EA) affects the colonization and pathogenicity of certain human bacterial pathogens in the gastrointestinal tract. However, EA can also affect the intracellular survival and replication of host cell invasive bacteria such as Listeria monocytogenes (LMO) and Salmonella enterica serovar Typhimurium (S. Typhimurium). The EA utilization (eut) genes can be categorized as regulatory, enzymatic, or structural, and previous work in LMO showed that loss of genes encoding functions for the enzymatic breakdown of EA inhibited LMO intracellular replication. In this work, we sought to further characterize the role of EA utilization during LMO infection of host …

Hemojuvelin-Mediated Hepcidin Induction Requires Both Bone Morphogenetic Protein Type I Receptors Alk2 And Alk3, Deniz Y Dogan, Eugen I Urzica, Isabelle Hornung, Philipp Kastl, David Oguama, Franca M Fette, Lien H Nguyen, Frank Rosenbauer, Kai Zacharowski, Ursula Klingmüller, Elise Gradhand, Andreas Von Knethen, Rüdiger Popp, Ingrid Fleming, Lisa Schrader, Andrea U Steinbicker

Faculty, Staff and Student Publications

Hemojuvelin (HJV) is a glycosylphosphatidylinositol-anchored protein of the repulsive guidance molecule family acting as a bone morphogenetic protein (BMP) coreceptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin, thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV)-mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp messenger RNA (mRNA) …

Slow Proliferation Of Bap1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling And Resistance To Nutrient Stress, Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J Purwin, Jelan I Haj, Francis J Waltrich, Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A Davies, Julio A Aguirre-Ghiso, Takami Sato, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and …

Tenovin-1, A Selective Sirt1/2 Inhibitor, Attenuates High-Fat Diet-Induced Hepatic Fibrosis Via Inhibition Of Hsc Activation In Zdf Rats, Swati Sharma, Sreevarsha Gali, Amit Kundu, Jae Hyeon Park, Jae-Sung Kim, Hyung Sik Kim

2020-Current year OA Pubs

Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-β1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 …

An Inducible Genetic Tool To Track And Manipulate Specific Microglial States Reveals Their Plasticity And Roles In Remyelination, Kia M Barclay, Nora Abduljawad, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A Mazzitelli, Leon C D Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, Jinchao Hou, Naresha Saligrama, Marco Colonna, Jonathan Kipnis, Qingyun Li, Et Al.

2020-Current year OA Pubs

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreER

Limited Nerve Regeneration Across Acellular Nerve Allografts (Anas) Coincides With Changes In Blood Vessel Morphology And The Development Of A Pro-Inflammatory Microenvironment, Jesús A Acevedo Cintrón, Daniel A Hunter, Lauren Schellhardt, Deng Pan, Susan E Mackinnon, Matthew D Wood

2020-Current year OA Pubs

The use of acellular nerve allografts (ANAs) to reconstruct long nerve gaps (>3 cm) is associated with limited axon regeneration. To understand why ANA length might limit regeneration, we focused on identifying differences in the regenerative and vascular microenvironment that develop within ANAs based on their length. A rat sciatic nerve gap model was repaired with either short (2 cm) or long (4 cm) ANAs, and histomorphometry was used to measure myelinated axon regeneration and blood vessel morphology at various timepoints (2-, 4- and 8-weeks). Both groups demonstrated robust axonal regeneration within the proximal graft region, which continued across …

Distinct Expression Patterns Of Hedgehog Signaling Components In Mouse Gustatory System During Postnatal Tongue Development And Adult Homeostasis, Archana Kumari, Nicole E Franks, Libo Li, Gabrielle Audu, Sarah Liskowicz, John D Johnson, Charlotte M Mistretta, Benjamin L Allen

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH …

Defining The Kras- And Erk-Dependent Transcriptome In Kras-Mutant Cancers, Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Alexey Sorokin, Preeti Marie Kanikarla, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der

Faculty, Staff and Student Publications

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and ERK-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges significantly from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome and other components of the cell cycle machinery as …

Hnrnpm Protects Against The Dsrna-Mediated Interferon Response By Repressing Line-Associated Cryptic Splicing, Rong Zheng, Mikayla Dunlap, Georg O M Bobkov, Carlos Gonzalez-Figueroa, Khushali J Patel, Jingyi Lyu, Samuel E Harvey, Tracey W Chan, Giovanni Quinones-Valdez, Mudra Choudhury, Charlotte A Le Roux, Mason D Bartels, Amy Vuong, Ryan A Flynn, Howard Y Chang, Eric L Van Nostrand, Xinshu Xiao, Chonghui Cheng

Faculty, Staff and Students Publications

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. …

Metabolic Regulator Errγ Governs Gastric Stem Cell Differentiation Into Acid-Secreting Parietal Cells, Mahliyah Adkins-Threats, Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y Hwang, Joseph R Burclaff, Shilpa Jain, Jason C Mills

Faculty, Staff and Students Publications

Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. Esrrg^P2ACreERT2 lineage tracing revealed Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially …

Cis-Regulatory Evolution Of The Recently Expanded Ly49 Gene Family, Changxu Fan, Xiaoyun Xing, Samuel J H Murphy, Jennifer Poursine-Laurent, Heather Schmidt, Bijal A Parikh, Jeesang Yoon, Mayank N K Choudhary, Naresha Saligrama, Sytse J Piersma, Wayne M Yokoyama, Ting Wang

2020-Current year OA Pubs

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from …

Trpv1 Analgesics Disturb Core Body Temperature Via A Biased Allosteric Mechanism Involving Conformations Distinct From That For Nociception, Yi-Zhe Huang, Jing-Xian Ma, Yu-Jing Bian, Qin-Ru Bai, Yu-Hao Gao, Shu-Ke Di, Yun-Tao Lei, Hui Yang, Xiao-Na Yang, Chang-Yan Shao, Wen-Hui Wang, Peng Cao, Chang-Zhu Li, Michael X Zhu, Meng-Yang Sun, Ye Yu

Faculty, Staff and Student Publications

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, …

Perturbations In Risk/Reward Decision Making And Frontal Cortical Catecholamine Regulation Induced By Mild Traumatic Brain Injury, Christopher P Knapp, Eleni Papadopoulos, Jessica A Loweth, Ramesh Raghupathi, Stan B Floresco, Barry D Waterhouse, Rachel L Navarra

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Mild traumatic brain injury (mTBI) disrupts cognitive processes that influence risk taking behavior. Little is known regarding the effects of repetitive mild injury (rmTBI) or whether these outcomes are sex specific. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is densely innervated by catecholaminergic fibers. Aberrant PFC catecholamine activity has been documented following TBI and may underlie TBI-induced risky behavior. The present study characterized the effects of rmTBI on risk/reward decision making behavior and catecholamine transmitter regulatory proteins within the PFC. Rats were exposed to sham, single (smTBI), or three closed-head controlled cortical impact (CH-CCI) injuries and …

Evaluation Of Copanlisib In Combination With Eribulin In Triple-Negative Breast Cancer Patient-Derived Xenograft Models, Zhanfang Guo, Jingqin Luo, R Jay Mashl, Jeremy Hoog, Piyush Maiti, Nikki Fettig, Sherri R Davies, Rebecca Aft, Jason M Held, Ramaswamy Govindan, Li Ding, Shunqiang Li, Cornelius Von Morze, Kooresh I Shoghi, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

UNLABELLED: The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were …

Sirt6 Protects Retinal Ganglion Cells And Optic Nerve From Degeneration During Aging And Glaucoma, Fan Xia, Shuizhen Shi, Erick Palacios, Wei Liu, Seth E Buscho, Joseph Li, Shixia Huang, Gianmarco Vizzeri, Xiaocheng Charlie Dong, Massoud Motamedi, Wenbo Zhang, Hua Liu

Faculty, Staff and Students Publications

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level …

Tl1a And Il-18 Synergy Promotes Gm-Csf-Dependent Thymic Granulopoiesis In Mice, Mario Ruiz Pérez, Kodi Ravichandran, Et Al.

2020-Current year OA Pubs

Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced …

Orthogonal Proteogenomic Analysis Identifies The Druggable Pa2g4-Myc Axis In 3q26 Aml, Matteo Marchesini, Andrea Gherli, Elisa Simoncini, Lucas Moron Dalla Tor, Anna Montanaro, Natthakan Thongon, Federica Vento, Chiara Liverani, Elisa Cerretani, Anna D'Antuono, Luca Pagliaro, Raffaella Zamponi, Chiara Spadazzi, Elena Follini, Benedetta Cambò, Mariateresa Giaimo, Angela Falco, Gabriella Sammarelli, Giannalisa Todaro, Sabrina Bonomini, Valentina Adami, Silvano Piazza, Claudia Corbo, Bruno Lorusso, Federica Mezzasoma, Costanza Anna Maria Lagrasta, Maria Paola Martelli, Roberta La Starza, Antonio Cuneo, Franco Aversa, Cristina Mecucci, Federico Quaini, Simona Colla, Giovanni Roti

Faculty, Staff and Student Publications

The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the …

Telomere Dysfunction Alters Intestinal Stem Cell Dynamics To Promote Cancer, Kyle A Labella, Wen-Hao Hsu, Jiexi Li, Yutao Qi, Yonghong Liu, Jingjing Liu, Chia-Chin Wu, Yang Liu, Zingzhi Song, Yiyun Lin, Jonathan M Blecher, Shan Jiang, Xiaoying Shang, Jincheng Han, Denise J Spring, Jianhua Zhang, Yan Xia, Ronald A Depinho

Faculty, Staff and Student Publications

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, …